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Dynamic balance of pro- and anti-inflammatory signals controls disease and limits pathology

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Abstract

Immune responses to pathogens are complex and not well understood in many diseases, and this is especially true for infections by persistent pathogens. One mechanism that allows for long‐term control of infection while also preventing an over‐zealous inflammatory response from causing extensive tissue damage is for the immune system to balance pro‐ and anti‐inflammatory cells and signals. This balance is dynamic and the immune system responds to cues from both host and pathogen, maintaining a steady state across multiple scales through continuous feedback. Identifying the signals, cells, cytokines, and other immune response factors that mediate this balance over time has been difficult using traditional research strategies. Computational modeling studies based on data from traditional systems can identify how this balance contributes to immunity. Here we provide evidence from both experimental and mathematical/computational studies to support the concept of a dynamic balance operating during persistent and other infection scenarios. We focus mainly on tuberculosis, currently the leading cause of death due to infectious disease in the world, and also provide evidence for other infections. A better understanding of the dynamically balanced immune response can help shape treatment strategies that utilize both drugs and host‐directed therapies.

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... Pro-and anti-inflammatory cytokines act in concert to balance the complex interplay of immune responses and maintain organism homeostasis [49]. We therefore tested the key pro-and anti-inflammatory cytokines IL1B and IL10, as well as the chemokine IL8, in their transcriptional regulation upon EMF exposure in LPS stimulated cells [49,50]. ...
... Pro-and anti-inflammatory cytokines act in concert to balance the complex interplay of immune responses and maintain organism homeostasis [49]. We therefore tested the key pro-and anti-inflammatory cytokines IL1B and IL10, as well as the chemokine IL8, in their transcriptional regulation upon EMF exposure in LPS stimulated cells [49,50]. While IL1B levels increased after 24 h in stEMF exposed THP1, IL10 levels were already 6-fold elevated after 1 h of exposure, suggesting anti-inflammatory rather than pro-inflammatory signaling as immediate responses induced by EMF (Figure 7a,b), which is in line with previous studies [13]. ...
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Innate immune cells react to electromagnetic fields (EMF) by generating reactive oxygen species (ROS), crucial intracellular messengers. Discrepancies in applied parameters of EMF studies, e.g., flux densities, complicate direct comparison of downstream anti-oxidative responses and immune regulatory signaling. We therefore compared the impact of different EMF flux densities in human leukemic THP1 cells and peripheral blood mononuclear cells (PBMC) of healthy donors to additionally consider a potential disparate receptivity based on medical origin. ROS levels increased in THP1 cells stimulated with lipopolysaccharide (LPS) after one hour of EMF exposure. Moreover, weak EMF mitigated the depletion of the reducing agent NAD(P)H in THP1. Neither of these effects occurred in PBMC. Landscaping transcriptional responses to varied EMF revealed elevation of the anti-oxidative enzymes PRDX6 (2-fold) and DHCR24 (6-fold) in THP1, implying involvement in lipid metabolism. Furthermore, our study confirmed anti-inflammatory effects of EMF by 6-fold increased expression of IL10. Strikingly, THP1 responded to weak EMF, while PBMC were primarily affected by strong EMF, yet with severe cellular stress and enhanced rates of apoptosis, indicated by HSP70 and caspase 3 (CASP3). Taken together, our results emphasize an altered susceptibility of immune cells of different origin and associate EMF-related effects with anti-inflammatory signaling and lipid metabolism.
... Anti-inflammatory cytokines are down-regulated as a result of proinflammatory cytokines being over-regulated. This occurrence indicates the severity for disease 10 . As a result, the immune system regulatory process aims to restore cytokine balance to normal homeostatic levels with no increase or decrease of any of them. ...
... Salmonids have the ability to elongate and desaturate FAs to fulfill their physiological needs (e.g., balance the proinflammatory and anti-inflammatory FA profile in the membranes) using the available dietary FAs (ω3 or ω6) (Leaver et al., 2008;Castro et al., 2012;Colombo et al., 2021). During immune stimulation (e.g., infection), a balance between pro-and anti-inflammatory responses of the host is required to minimize cellular damage caused by immune responses (Cicchese et al., 2018). Herein, we examined the effects of two diets formulated with 0.4% EPA + DHA and either high-ω3 or high-ω6 fed to salmon for 8 weeks, and a third group that was fed the high-ω6 diet for 4 weeks followed by 4 weeks of the high-ω3 diet (i.e., the "switched-diet" group) on the head kidney immune response. ...
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We investigated the immunomodulatory effect of varying levels of dietary ω6/ω3 fatty acids (FA) on Atlantic salmon (Salmo salar) antibacterial response. Two groups were fed either high-18:3ω3 or high-18:2ω6 FA diets for 8-weeks, and a third group was fed for 4-weeks on the high-18:2ω6 diet followed by 4-weeks on the high-18:3ω3 diet and termed “Switched-diet”. Following the second 4-weeks of feeding (i.e., at 8-weeks), head kidney tissues from all groups were sampled for FA analysis. Fish were then intraperitoneally injected with either a formalin-killed Renibacterium salmoninarum bacterin (5 × 107 cells mL-1) or phosphate-buffered saline (PBS control), and head kidney tissues for gene expression analysis were sampled at 24 h post-injection. FA analysis showed that the head kidney profile reflected the dietary FA, especially for C18 FAs. The qPCR analyses of twenty-three genes showed that both high-ω6 and high-ω3 groups had significant bacterin-dependent induction of some transcripts involved in lipid metabolism (ch25ha and lipe), pathogen recognition (clec12b and tlr5), and immune effectors (znrf1and cish). In contrast, these transcripts did not significantly respond to the bacterin in the “Switched-diet” group. Concurrently, biomarkers encoding proteins with putative roles in biotic inflammatory response (tnfrsf6b) and dendritic cell maturation (ccl13) were upregulated, and a chemokine receptor (cxcr1) was downregulated with the bacterin injection regardless of the experimental diets. On the other hand, an inflammatory regulator biomarker, bcl3 was only significantly upregulated in the high-ω3 fed group and a C‑type lectin family member (clec3a) was only significantly downregulated in the Switched-diet group with the bacterin injection (compared with diet-matched PBS injected controls). Transcript fold-change (FC: bacterin/PBS) showed that tlr5 was significantly over 2-fold higher in high-18:2ω6 compared with both other diet groups. FC and FA associations highlighted the role of DGLA (20:3ω6; anti-inflammatory) and/or EPA (20:5ω3; anti-inflammatory) vs. ARA (20:4ω6; pro-inflammatory), as representative of the anti-inflammatory/pro-inflammatory balance between eicosanoid precursors. Also, the correlations revealed associations of FA proportions (% total FA) and FA ratios with several eicosanoid and immune receptor biomarkers (e.g., DGLA/ARA significant positive correlation with pgds, 5loxa, 5loxb, tlr5, and cxcr1). In summary, dietary FA profiles and/or regimen modulated the expression of some immune-relevant genes in Atlantic salmon injected with R. salmoninarum bacterin. The modulation of Atlantic salmon responses to bacterial pathogens and their associated antigens using high-ω6/high-ω3 diets warrants further investigation.
... This acetylcholine interacts with the nicotinic acetylcholine receptor subunit α7 (α7nAChR) expressed on the membrane of the innate immune cells to stop the secretion of pro-inflammatory cytokines [7][8][9][10]. As a result, this avoids an over exposure to pro-inflammatory cytokines, as that may damage tissue, impair organ function and could even be lethal [11,12]. ...
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Heart rate variability (HRV) is a known measure of cardiac autonomic function. A cardiovascular autonomic dysfunction (CAD), measured as changes in HRV, is usually presented after an infectious process. The aim of the present study is to assess the association between serum inflammatory markers and CAD. For this purpose, 50 volunteers (13 of them recovering from an infection) were recruited and followed-up for 6 weeks. Their serum inflammatory biomarkers (CRP, IL1, IL4, IL6, IL10, and TNFalpha) were quantified throughout those weeks, along with their HRV resting, in response to the Valsalva maneuver, metronome breathing, standing and sustained handgrip. The correlation of within-subject changes in both HRV and inflammatory biomarkers was assessed to evaluate the concurrent changes. An inverse within-subject correlation was found between CRP and HRV in response to the Valsalva maneuver (rho (95% CI): −0.517 (−0.877 to −0.001); p = 0.032) and HRV standing (rho (95% CI): −0.490 (−0.943 to −0.036); p = 0.034). At the beginning, increased values of CRP are found along with reduced levels of HRV. Then, the CRP was reduced, accompanied by an improvement (increase) in HRV. These results suggest that CRP is a potential marker of CAD. Whether it is the cause, the consequence or a risk indicator non-causally associated is still to be determined.
... Understanding the sequence and tempo of the host response to SARS-CoV-2 infection seems most important, because cells involved in the inflammatory and the immune response, and the cytokines produced by these cells that play a key role in the response change enormously depending on the phase of the response. 9,12,13 Cell interaction which may determine the direction of the host response in the course of COVID-19 from asymptomatic to the severe phase has been studied previously mainly with interaction between different classes of macrophages and lymphocytes, and various hypotheses have been proposed in consideration of these cells to explain the mechanisms that differentiate severe disease from mild or moderate. However, recent studies using scRNA-seq suggests that neutrophils are also one of the main players in the host response to COVID-19, 14 although these cells have been overlooked as an immunological coordinator in the host response to infections. ...
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Prevention of the disease severity seems critical for mortality reduction of Coronavirus (CoV) disease‐19. The neutrophils play a key role in the induction of severity. We here propose inhibition of neutrophil activation and/or cascade reactions of complement leading to this cell activation at the early phase of the disease as a potential tool to inhibit aggravation of the disease. We emphasize the need of appropriate timing for intervention as follows. 1) The intervention at the very early stage of severe acute respiratory syndrome‐CoV‐2 infection may harm the defensive host response to the infection because of a critical function of neutrophils in this response, and 2) intervention at too late a stage will not stop the infiltration of fully activated neutrophils that produce large amounts of toxic substances. This article is protected by copyright. All rights reserved.
... In the context of aSAH recovery, an understanding of the relative trajectory of this balance remains important but not well considered. Furthermore, the balance between pro-and anti-inflammatory cytokines differs at the molecular, organ, and whole-host levels [15]. Similar questions concerning this balance have been investigated in conditions such as generalized anxiety spectrum disorder (GAD) and multiple myeloma (MM). ...
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Aneurysmal subarachnoid hemorrhage (aSAH) is a severe form of stroke that occurs following rupture of a cerebral aneurysm. Acute inflammation and secondary delayed inflammatory responses, both largely controlled by cytokines, work together to create high mortality and morbidity for this group. The trajectory and time course of cytokine change must be better understood in order to effectively manage unregulated inflammation and improve patient outcomes following aSAH. A systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Three different search phrases (“cytokines and subarachnoid hemorrhage,” “cytokine levels and subarachnoid hemorrhage,” and “cytokine measurement and subarachnoid hemorrhage”) were applied across three databases (PubMed, SCOPUS, and the Cochrane Library). Our procedures returned 856 papers. After application of inclusion/exclusion criteria, 95 preclinical animal studies and 41 clinical studies remained. Across studies, 22 different cytokines had been investigated, 5 different tissue types were analyzed, and 3 animal models were utilized. Three main pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) demonstrated reliable increases following aSAH across the included studies. While this is a promising area of research for potential therapeutics, there are gaps in the knowledge base that bar progress for clinical translation of this information. In particular, there is a need for investigations that explore the systemic inflammatory response following injury in a more diverse number of cytokines, the balance of specific pro-/anti- inflammatory cytokines, and how these biomarkers relate to patient outcomes and recovery over time.
... They act as a critical mediator by providing homeostasis and thereby maintaining the immune system of the host (Lippitz 2013). In healthy individuals, the equilibrium between pro-and antiinflammatory cytokines are maintained (Cicchese et al. 2018). Generally, the expression of cytokines interplays between pro-and anti-inflammatory genes in the host system. ...
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Aeromonas hydrophila is an opportunistic bacterial fish pathogen causing huge economic losses in aquaculture farms. Present work explored the pathophysiological effects of experimental A. hydrophila Ah17 under sublethal dose (1 × 105 CFU/ml, 500 μl) in Channa striata. Experiments revealed higher A. hydrophila Ah17 load in muscle tissue and lower in the kidney tissue. Haematological parameters and total serum protein level were significantly decreased in A. hydrophila Ah17 infected group when compared to the control group. Elevation of liver enzyme markers (AST, ALT and ALP) were noticed in infected group. Antioxidant genes (Cat, MnSOD and GPx) were highly expressed in liver tissue compared to the head kidney. Immune regulatory gene IL-8 was significantly downregulated and TGF-β was upregulated in head kidney and spleen tissues. Imbalanced swimming conditions, changes in pectoral fin movement, caudal fin injury, dorsal and ventral ulceration on body parts, haemorrhagic lesions and white foci in the liver were noticed during A. hydrophila Ah17 infection. Thus, the present study demonstrated the pathophysiological effects of A. hydrophila Ah17 against economically important snakehead murrel C. striata under sublethal conditions.
... Our previous analysis showed much stronger inflammation in Mm compared to Mf, which launches extensive measures to control cell proliferation. The balance between these pro-and antiinflammatory mechanisms appears to be the key to resilience, and a deeper understanding of the underlying mechanisms is therefore of utmost importance (Cicchese et al., 2018). The energy-intensive nature of these processes makes metabolic processes like glycolysis and tryptophan (Trp) metabolism close accomplices in regulating the overall physiological dynamics. ...
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Malaria has a complex pathology with varying manifestations and symptoms, effects on host tissues, and different degrees of severity and ultimate outcome, depending on the causative Plasmodium pathogen and host species. Previously, we compared the peripheral blood transcriptomes of two macaque species ( Macaca mulatta and Macaca fascicularis ) in response to acute primary infection by Plasmodium knowlesi . Although these two species are very closely related, the infection in M. mulatta is fatal, unless aggressively treated, whereas M. fascicularis develops a chronic, but tolerable infection in the blood. As a reason for this stark difference, our analysis suggests delayed pathogen detection in M. mulatta followed by extended inflammation that eventually overwhelms this monkey’s immune response. By contrast, the natural host M. fascicularis detects the pathogen earlier and controls the inflammation. Additionally, M. fascicularis limits cell proliferation pathways during the log phase of infection, presumably in an attempt to control inflammation. Subsequent cell proliferation suggests a cell-mediated adaptive immune response. Here, we focus on molecular mechanisms underlying the key differences in the host and parasite responses and their coordination. SICAvar Type 1 surface antigens are highly correlated with pattern recognition receptor signaling and important inflammatory genes for both hosts. Analysis of pathogen detection pathways reveals a similar signaling mechanism, but with important differences in the glutamate G-protein coupled receptor (GPCR) signaling pathway. Furthermore, differences in inflammasome assembly processes suggests an important role of S100 proteins in balancing inflammation and cell proliferation. Both differences point to the importance of Ca ²⁺ homeostasis in inflammation. Additionally, the kynurenine-to-tryptophan ratio, a known inflammatory biomarker, emphasizes higher inflammation in M. mulatta during log phase. Transcriptomics-aided metabolic modeling provides a functional method for evaluating these changes and understanding downstream changes in NAD metabolism and aryl hydrocarbon receptor (AhR) signaling, with enhanced NAD metabolism in M. fascicularis and stronger AhR signaling in M. mulatta . AhR signaling controls important immune genes like IL6, IFNγ and IDO1. However, direct changes due to AhR signaling could not be established due to complicated regulatory feedback mechanisms associated with the AhR repressor (AhRR). A complete understanding of the exact dynamics of the immune response is difficult to achieve. Nonetheless, our comparative analysis provides clear suggestions of processes that underlie an effective immune response. Thus, our study identifies multiple points of intervention that are apparently responsible for a balanced and effective immune response and thereby paves the way toward future immune strategies for treating malaria.
... Many of these proteins are part of the pro-inflammatory and not of the antiinflammatory system. This is an intriguing finding in COVID-19, considering pro-and anti-inflammatory pathways are engaged at the same time in most other disease states (21). ...
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Multiple studies have investigated the role of blood circulating proteins in COVID-19 disease using the Olink affinity proteomics platform. However, study inclusion criteria and sample collection conditions varied between studies, leading to sometimes incongruent associations. To identify the most robust protein markers of the disease and the underlying pathways that are relevant under all conditions, it is essential to identify proteins that replicate most widely. Here we combined the Olink proteomics profiles of two newly recruited COVID-19 studies (N=68 and N=98) with those of three previously published COVID-19 studies (N=383, N=83, N=57). For these studies, three Olink panels (Inflammation and Cardiovascular II & III) with 253 unique proteins were compared. Case/ control analysis revealed thirteen proteins (CCL16, CCL7, CXCL10, CCL8, LGALS9, CXCL11, IL1RN, CCL2, CD274, IL6, IL18, MERTK, IFNg, and IL18R1) that were differentially expressed in COVID-19 patients in all five studies. Except CCL16, which was higher in controls, all proteins were overexpressed in COVID-19 patients. Pathway analysis revealed concordant trends across all studies with pathways related to cytokine- cytokine interaction, IL18 signaling, fluid shear stress and rheumatoid arthritis. Our results reaffirm previous findings related to a COVID-19 cytokine storm syndrome. Cross-study robustness of COVID-19 specific protein expression profiles support the utility of affinity proteomics as a tool and for the identification of potential therapeutic targets.
... In our model the number of AEC ( _ L) is influenced by the lysis induced by fungal hyphae and the damage originating from active AM and neutrophils. The tissue damage by immune cells is often ignored in computational models, but is crucial to understand recruitment and, in particular, depletion of immune cells [68]. To this end, we further connect tissue damage with the pro-inflammatory cytokine level C: ...
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Aspergillus fumigatus is an important human fungal pathogen and its conidia are constantly inhaled by humans. In immunocompromised individuals, conidia can grow out as hyphae that damage lung epithelium. The resulting invasive aspergillosis is associated with devastating mortality rates. Since infection is a race between the innate immune system and the outgrowth of A. fumigatus conidia, we use dynamic optimization to obtain insight into the recruitment and depletion of alveolar macrophages and neutrophils. Using this model, we obtain key insights into major determinants of infection outcome on host and pathogen side. On the pathogen side, we predict in silico and confirm in vitro that germination speed is an important virulence trait of fungal pathogens due to the vulnerability of conidia against host defense. On the host side, we found that epithelial cells, which have been underappreciated, play a role in fungal clearance and are potent mediators of cytokine release. Both predictions were confirmed by in vitro experiments on established cell lines as well as primary lung cells. Further, our model affirms the importance of neutrophils in invasive aspergillosis and underlines that the role of macrophages remains elusive. We expect that our model will contribute to improvement of treatment protocols by focusing on the critical components of immune response to fungi but also fungal virulence traits.
... Under normal physiological conditions classically activated (M1) macrophages secrete pro-inflammatory factors such as TNFa, interleukin-6, and IL-1b, while alternatively activated (M2) macrophages show an anti-inflammatory phenotype (123,124). Additionally, regulatory T cells (T regs ) and type 2 T helper (T h 2) cells secrete anti-inflammatory factors (125). These cells maintain the homeostasis of the immune microenvironment. ...
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Mesenchymal stem cell-derived exosomes have been under investigation as potential treatments for a diverse range of diseases, and many animal and clinical trials have achieved encouraging results. However, it is well known that the biological activity of the exosomes is key to their therapeutic properties; however, till date, it has not been completely understood. Previous studies have provided different explanations of therapeutic mechanisms of the exosomes, including anti-inflammatory, immunomodulatory, and anti-aging mechanisms. The pathological effects of oxidative stress often include organ damage, inflammation, and disorders of material and energy metabolism. The evidence gathered from research involving animal models indicates that exosomes have antioxidant properties, which can also explain their anti-inflammatory and cytoprotective effects. In this study, we have summarized the antioxidant effects of exosomes in in vivo and in vitro models, and have evaluated the anti-oxidant mechanisms of exosomes by demonstrating a direct reduction in excessive reactive oxygen species (ROS), promotion of intracellular defence of anti-oxidative stress, immunomodulation by inhibiting excess ROS, and alteration of mitochondrial performance. Exosomes exert their cytoprotective and anti-inflammatory properties by regulating the redox environment and oxidative stress, which explains the therapeutic effects of exosomes in a variety of diseases, mechanisms that can be well preserved among different species.
... Fertility depends upon a correct balance between pro-and anti-inflammatory components, warranting homeostasis [5,6]. Inflammation is a part of relevant steps of reproductive physiology, present during ovulation, mating, sperm tolerance, placentation, or parturition [7]. ...
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Uterine homeostasis is maintained after mating by eliminating pathogens, foreign cells, and proteins by a transient inflammation of the uterus. Such inflammation does not occur in the oviductal sperm reservoir (utero-tubal junction, UTJ), colonized by a population of potentially fertile spermatozoa before the inflammatory changes are triggered. Semen entry (spermatozoa and/or seminal plasma) modifies the expression of regulatory genes, including cell proliferation and differentiation-related transcripts. Considering pigs display a fractionated ejaculation, this study aims to determine whether different ejaculate fractions differentially modulate cell proliferation and differentiation-related transcripts in the sow reproductive tract during the peri-ovulatory stage. Using species-specific microarray analyses, the differential expression of 144 cell proliferation and differentiation-related transcripts was studied in specific segments: cervix (Cvx), distal and proximal uterus (DistUt, ProxUt), UTJ, isthmus (Isth), ampulla (Amp), and infundibulum (Inf) of the peri-ovulatory sow reproductive tract in response to semen and/or seminal plasma cervical deposition. Most mRNA expression changes were induced by mating. In addition, while mating upregulates the fibroblast growth factor 1 (FGF1, p-value DistUt = 0.0007; ProxUt = 0.0253) transcript in the endometrium, both its receptor, the fibroblast growth factor receptor 1 (FGFR1, p-value DistUt = 2.14 e−06; ProxUt = 0.0027; UTJ = 0.0458) transcript, and a potentiator of its biological effect, the fibroblast growth factor binding protein 1 (FGFBP1), were downregulated in the endometrium (p-value DistUt = 0.0068; ProxUt = 0.0011) and the UTJ (p-value UTJ = 0.0191). The FGFBP1 was downregulated in the whole oviduct after seminal depositions (p-value Isth = 0.0007; Amp = 0.0007; Inf = 6.87 e−05) and, interestingly, FGFR1 was downregulated in the endometrium in the absence of semen (p-value DistUt = 0.0097; ProxUt = 0.0456). In conclusion, the findings suggest that spermatozoa, seminal components, and the act of mating trigger, besides inflammation, differential mechanisms in the peri-ovulatory female reproductive tract, relevant for tissue repair.
... Classical monocytes in our study were reduced in preterm infants. A balanced pro-inflammatory response is crucial to controlling infectious pathogens (12). Therefore, given the importance of classical monocytes in phagocytosis, producing early proinflammatory cytokines (IL-1b, IL-6, and TNF-a) and chemokines (IL-8, eotaxin, macrophage inflammatory proteins) and T-cell activation, their reduction in preterm infants is likely detrimental during infection (13). ...
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Background Preterm infants are highly vulnerable to infectious disease. While many factors are likely to contribute to this enhanced susceptibility, the immature nature of the preterm immune system is postulated as one key factor. Methods In our study, we used high-dimensional flow cytometry and cytokine assays to characterise the immune profiles in 25 preterm (range: 30.4-34.1 weeks gestational age) and 25 term infant (range: 37-40 weeks gestational age) cord blood samples. Results We found that preterm infants exhibit reduced frequencies of monocytes, CD56 bright NK cells, CD8+ T-cells, γδ T-cells and an increased frequency of intermediate monocytes, CD4+ T-cells, central memory CD4+ and CD8+ T-cells, Tregs and transitional B-cells compared to term infants. Pro-inflammatory cytokines IL-1β, IL-6 and IL-17A were lower in preterm infants in addition to chemokines IL-8, eotaxin, MIP-1α and MIP-1β. However, IL-15 and MCP-1 were higher in preterm infants. Conclusion Overall, we identify key differences in pro-inflammatory immune profiles between preterm and term infants. These findings may help to explain why preterm infants are more susceptible to infectious disease during early life and facilitate the development of targeted interventions to protect this highly vulnerable group.
... The inflammatory response was identified early on as a potential driver of COVID-19 outcomes due to existing research in SARS and emerging research in COVID-19. While too low of an inflammatory response is a concern because it will fail to eliminate the immune threat (139), excessive proinflammatory cytokine activity can cascade (140) and cause cell damage, among other problems (141). A dysregulated immune response can cause significant damage to the host (142)(143)(144), including pathogenesis associated with sepsis. ...
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The novel coronavirus SARS-CoV-2, which emerged in late 2019, has since spread around the world and infected hundreds of millions of people with coronavirus disease 2019 (COVID-19). While this viral species was unknown prior to January 2020, its similarity to other coronaviruses that infect humans has allowed for rapid insight into the mechanisms that it uses to infect human hosts, as well as the ways in which the human
... [122][123][124] The balance between these two contrasting yet complementary states of immunity is central for reinstating tissue homeostasis. 125,126 A shift toward either side can be detrimental and result in immune pathology and tissue damage. ...
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Background: Coronaviruses (CoVs) are single-stranded, polyadenylated, enveloped RNA of positive polarity with a unique potential to alter host tropism. This has been exceptionally demonstrated by the emergence of deadly virus outbreaks of the past: Severe Acute Respiratory Syndrome (SARS-CoV) in 2003 and Middle East Respiratory Syndrome (MERS-CoV) in 2012. Summary: The 2019 outbreak by the new cross-species transmission of SARS-CoV-2 has put the world on alert. CoV infection is triggered by receptor recognition, membrane fusion, and successive viral entry mediated by the surface Spike (S) glycoprotein. S protein is one of the major antigenic determinants and the target for neutralizing antibodies. It is a valuable target in antiviral therapies because of its central role in cell-cell fusion, viral antigen spread, and host immune responses leading to immunopathogenesis. The receptor-binding domain of S protein has received greater attention as it initiates host attachment and contains major antigenic determinants. However, investigating the therapeutic potential of fusion peptide as a part of the fusion core complex assembled by the heptad repeats 1 and 2 (HR1 and HR2) is also warranted. Along with receptor attachment and entry, fusion mechanisms should also be explored for designing inhibitors as a therapeutic intervention. Key message: In this article, we review the S protein function and its role in mediating membrane fusion, spread, tropism, and its associated pathogenesis with notable therapeutic strategies focusing on results obtained from studies on a murine β-Coronavirus (m-CoV) and its associated disease process.
... Likewise, the inflammatory response depends on the balance between pro-and anti-inflammatory signals. However, when that equilibrium is disturbed, a more widespread inflammatory response may take place [52]. ...
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The goal of this study was to explore the specific signaling pathways related to inflammation in two experimental mouse dry eye (EDE) models. Female C57BL/6 mice housed for 10 days in a controlled desiccative environment were either treated with scopolamine (EDE-1; n = 18) or subjected to extraorbital lacrimal gland excision bilaterally (EDE-2; n = 10). Non-induced mice (n = 20) served as healthy controls. A corneal fluorescein staining (CFS) scoring was used at baseline through to day (D) 10 to evaluate epitheliopathy. At D10, corneas and conjunctivas were collected for multiplexed transcriptomic analysis with the NanoString® mouse inflammatory CodeSet. Both EDE-1 and EDE-2 mice presented a change in corneal integrity, with a significant increase in CFS scores at D10. More gene transcripts were identified in EDE-2 compared with EDE-1 (116 vs. 96, respectively), and only a few were common to both models, 13 for the cornea and 6 for the conjunctiva. The gene functional annotation analysis revealed that the same inflammatory pathways were involved in both models. Comparative profiling of gene expression in the two EDE models leads to the identification of various targets and signaling pathways, which can be extrapolated to and confirmed in human disease.
... However, other work suggests a more complicated picture (5,18,19). Finally, it is likely that a balance of pro-and anti-inflammatory molecules works to maintain long term control of infection during chronic infections (20). It could be that neutrophils, which can produce both pro-and anti-inflammatory cytokines (21), may tip the granuloma environment toward a more bacteria-permissive space. ...
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Neutrophil infiltration into tuberculous granulomas is often associated with higher bacteria loads and severe disease but the basis for this relationship is not well understood. To better elucidate the connection between neutrophils and pathology in primate systems, we paired data from experimental studies with our next generation computational model GranSim to identify neutrophil-related factors, including neutrophil recruitment, lifespan, and intracellular bacteria numbers, that drive granuloma-level outcomes. We predict mechanisms underlying spatial organization of neutrophils within granulomas and identify how neutrophils contribute to granuloma dissemination. We also performed virtual deletion and depletion of neutrophils within granulomas and found that neutrophils play a nuanced role in determining granuloma outcome, promoting uncontrolled bacterial growth in some and working to contain bacterial growth in others. Here, we present three key results: We show that neutrophils can facilitate local dissemination of granulomas and thereby enable the spread of infection. We suggest that neutrophils influence CFU burden during both innate and adaptive immune responses, implying that they may be targets for therapeutic interventions during later stages of infection. Further, through the use of uncertainty and sensitivity analyses, we predict which neutrophil processes drive granuloma severity and structure.
... Similar markers are derived from these common pathways. For example, NO level is associated with vasoconstriction [146], pro-inflammatory and cellmediated immunity (CMI) cytokines, HMGB1, IL-33, neopterin, ICAM1, and complement components are most related to inflammation and infection [147][148][149]. Lead, cadmium, oxidative stress, and MMPs are related to cell damage [64,93]. ...
Article
Thromboangiitis obliterans (TAO) or Buerger’s disease is a segmental inflammatory, thrombotic occlusive peripheral vascular disease with unknown aetiology that usually involves the medium and small-sized vessels of young male smokers. Due to its unknown aetiology and similarities with atherosclerosis and vasculitis, TAO diagnosis is still challenging. We aimed to review the status of biomolecular and laboratory para-clinical markers in TAO compared to atherosclerosis and vasculitis. We reported that, although some biomarkers might be common in TAO, atherosclerosis, and vasculitis, each disease occurs through a different pathway and, to our knowledge, there is no specific and definitive marker for differentiating TAO from atherosclerosis or vasculitis. Our review highlighted that pro-inflammatory and cell-mediated immunity cytokines, IL-33, HMGB1, neopterin, MMPs, ICAM1, complement components, fibrinogen, oxidative stress, NO levels, eNOS polymorphism, adrenalin and noradrenalin, lead, cadmium, and homocysteine are common markers. Nitric oxide, MPV, TLRs, MDA, ox-LDL, sST2, antioxidant system, autoantibodies, and type of infection are differential markers, whereas platelet and leukocyte count, haemoglobin, lipid profile, CRP, ESR, FBS, creatinine, d-dimer, hypercoagulation activity, as well as protein C and S are controversial markers. Finally, our study proposed diagnostic panels for laboratory differential diagnosis to be considered at first and in more advanced stages.
... Th1 cytokine production is crucial to eliminating M. tuberculosis from the host [117]; conversely, regulatory Th2 cell responses promote M. tuberculosis survival in the host [69,88]. Increased Th1 responses cause inflammation in host tissue [118], suggesting that a balanced Th1 and Th2 response is vital for the recovery of TB patients. The microbiome and other factors influence the complex interactions between the host defense response and M. tuberculosis survival mechanisms. ...
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Trillions of beneficial and hostile microorganisms live in the human respiratory and gastrointestinal tracts, which act as gatekeepers in maintaining human health, i.e., protecting the body from pathogens by colonizing mucosal surfaces with microbiota-derived antimicrobial metabolites such as short-chain fatty acids or host-derived cy-tokines and chemokines. It is widely accepted that the microbiome interacts with each other and with the host in a mutually beneficial relationship. Microbiota in the respiratory tract may also play a crucial role in immune homeostasis, maturation, and maintenance of respiratory physiology. Anti-TB antibiotics may cause dysbiosis in the lung and intestinal microbiota, affecting colonization resistance and making the host more susceptible to Mycobacterium tuberculosis (M. tuberculosis) infection. This review discusses recent advances in our understanding of the lung microbiota composition, the lungs and intestinal microbiota related to respiratory health and diseases , microbiome sequencing and analysis, the bloodstream, and the lymphatic system that underpin the gut-lung axis in M. tuberculosis-infected humans and animals. We also discuss the gut-lung axis interactions with the immune system, the role of the microbiome in TB pathogenesis, and the impact of anti-TB antibiotic therapy on the microbiota in animals, humans, and drug-resistant TB individuals.
... Th1 cytokine production is crucial to eliminating M. tuberculosis from the host [117]; conversely, regulatory Th2 cell responses promote M. tuberculosis survival in the host [69,88]. Increased Th1 responses cause inflammation in host tissue [118], suggesting that a balanced Th1 and Th2 response is vital for the recovery of TB patients. The microbiome and other factors influence the complex interactions between the host defense response and M. tuberculosis survival mechanisms. ...
Article
Trillions of beneficial and hostile microorganisms live in the human respiratory and gastrointestinal tracts, which act as gatekeepers in maintaining human health, i.e., protecting the body from pathogens by colonizing mucosal surfaces with microbiota-derived antimicrobial metabolites such as short-chain fatty acids or host-derived cytokines and chemokines. It is widely accepted that the microbiome interacts with each other and with the host in a mutually beneficial relationship. Microbiota in the respiratory tract may also play a crucial role in immune homeostasis, maturation, and maintenance of respiratory physiology. Anti-TB antibiotics may cause dysbiosis in the lung and intestinal microbiota, affecting colonization resistance and making the host more susceptible to Mycobacterium tuberculosis (M. tuberculosis) infection. This review discusses recent advances in our understanding of the lung microbiota composition, the lungs and intestinal microbiota related to respiratory health and diseases, microbiome sequencing and analysis, the bloodstream, and the lymphatic system that underpin the gut-lung axis in M. tuberculosis-infected humans and animals. We also discuss the gut-lung axis interactions with the immune system, the role of the microbiome in TB pathogenesis, and the impact of anti-TB antibiotic therapy on the microbiota in animals, humans, and drug-resistant TB individuals.
... Th1 cytokine production is crucial to eliminating M. tuberculosis from the host [117]; conversely, regulatory Th2 cell responses promote M. tuberculosis survival in the host [69,88]. Increased Th1 responses cause inflammation in host tissue [118], suggesting that a balanced Th1 and Th2 response is vital for the recovery of TB patients. The microbiome and other factors influence the complex interactions between the host defense response and M. tuberculosis survival mechanisms. ...
Article
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Trillions of beneficial and hostile microorganisms live in the human respiratory and gastrointestinal tracts, which act as gatekeepers in maintaining human health, i.e., protecting the body from pathogens by colonizing mucosal surfaces with microbiota-derived antimicrobial metabolites such as short-chain fatty acids or host-derived cy-tokines and chemokines. It is widely accepted that the microbiome interacts with each other and with the host in a mutually beneficial relationship. Microbiota in the respiratory tract may also play a crucial role in immune homeostasis, maturation, and maintenance of respiratory physiology. Anti-TB antibiotics may cause dysbiosis in the lung and intestinal microbiota, affecting colonization resistance and making the host more susceptible to Mycobacterium tuberculosis (M. tuberculosis) infection. This review discusses recent advances in our understanding of the lung microbiota composition, the lungs and intestinal microbiota related to respiratory health and diseases , microbiome sequencing and analysis, the bloodstream, and the lymphatic system that underpin the gut-lung axis in M. tuberculosis-infected humans and animals. We also discuss the gut-lung axis interactions with the immune system, the role of the microbiome in TB pathogenesis, and the impact of anti-TB antibiotic therapy on the microbiota in animals, humans, and drug-resistant TB individuals.
... Learning from the schistosome vaccine model, immune priming in skin and sdLNs together with immune priming in the lung and lung draining lymph nodes is essential for acquired protection. This action ensures that immune response is largely dependent on Th1 cells (Cicchese et al. 2018). ...
Article
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Schistosomiasis, also known as snail fever or bilharziasis, is a worm infection caused by trematode called schistosomes that affects humans and animals worldwide. Schistosomiasis endemically exists in developing countries. Inflammatory responses elicited in the early phase of infection represent the rate limiting step for parasite migration and pathogenesis and could be a valuable target for therapeutic interventions. Prostaglandin E2 (PGE2) and interleukin (IL)-10 were found to be differentially affected in case of immune-modulation studies and cytokine analysis of hosts infected with either normal or radiation-attenuated parasite (RA) which switches off the development of an effective immune response against the migrating parasite in the early phase of schistosomiasis. Normal parasites induce predominantly a T helper 2 (Th2)-type cytokine response (IL-4 and IL-5) which is essential for parasite survival; here, we discuss in detail the downstream effects and cascades of inflammatory signaling of PGE2 and IL10 induced by normal parasites and the effect of blocking PGE2 receptors. We suggest that by selectively constraining the production of PGE2 during vaccination or therapy of susceptible persons or infected patients of schistosomiasis, this would boost IL-12 and reduce IL-10 production leading to a polarization toward the anti-worm Thl cytokine synthesis (IL-2 and Interferon (IFN)-γ).
... A successful host immune response is generally the results of a dynamic balance between pro-and anti-inflammatory elements, with the ultimate goal of clearing the pathogen and limiting host damage [89]. qPCR analysis of TLR4, IL-6, TNF-α and TGF-β was performed to investigate the effects of OTA and CIT on the innate immune response of the mammary epithelium. ...
Article
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Frequent detection of mycotoxins ochratoxin A (OTA) and citrinin (CIT) in ruminant feed and feedstuff can be a potential threat to feed safety, animal performance and health. Ineffective biodegradation of these mycotoxins by rumen microflora following ingestion of contaminated feeds can lead to their circulatory transport to tissues such as mammary gland as the result of their biodistribution throughout the body. The bovine mammary epithelium plays a pivotal role in maintaining milk yield and composition and contributes to innate immune defense of the udder. The present study is the first to investigate individual effects of OTA and CIT on barrier and innate immune functions of the bovine mammary epithelium using a bovine mammary epithelial cell line (MAC-T). Results indicated that OTA and CIT exposure for 48 h significantly decreased cell viability in a concentration-dependent manner (p < 0.05). A decrease in transepithelial electrical resistance and increase in paracellular flux of FITC-40 kDa dextran was significantly induced by OTA treatment (p < 0.05), but not by CIT after 48 h exposure. qPCR was performed for assessment of expression of tight-junction proteins, Toll-like receptor 4 (TLR4) and cytokines after 4, 24 and 48 h of exposure. Both OTA and CIT markedly downregulated expression of claudin 3 and occludin (p < 0.05), whereas CIT did not affect zonula occludens-1 expression. Expression of TLR4 was significantly upregulated by OTA (p < 0.001) but downregulated by CIT (p < 0.05) at 48 h. Expression of IL-6, TNF-a and TGF-β was significantly upregulated by OTA (p < 0.05), whereas IL-6 and TGF-β expression was downregulated by CIT (p < 0.01). These results suggest that OTA and CIT could potentially differentially modulate barrier and innate immune functions of mammary epithelium. The present study not only throws light on the individual toxicity of each mycotoxin on bovine mammary epithelium but also lays the foundation for future studies on the combined effects of the two mycotoxins.
... Furthermore, the current study suggests the need to simultaneously evaluate pro-and counterinflammatory responses in future investigations of the inflammatory consequences of sleep deficiency, as this provides a more complete understanding of inflammatory dysregulation or imbalance, especially given that increases in IL-6 and CRP not always reflect an inflammatory response (67). Of note, evidence suggests that the maintenance of inflammatory balance of predominantly pro-and counterinflammatory signals is critical in disease control (68). Thus, both reduced and increased inflammatory responses to sleep disturbance can potentially affect health. ...
Article
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Sleep disturbances, including disrupted sleep and short sleep duration, are highly prevalent and are prospectively associated with an increased risk for various widespread diseases, including cardiometabolic, neurodegenerative, chronic pain, and autoimmune diseases. Systemic inflammation, which has been observed in populations experiencing sleep disturbances, may mechanistically link disturbed sleep with increased disease risks. To determine whether sleep disturbances are causally responsible for the inflammatory changes reported in population-based studies, we developed a 19-day in-hospital experimental model of prolonged sleep disturbance inducing disrupted and shortened sleep. The model included delayed sleep onset, frequent nighttime awakenings, and advanced sleep offset, interspersed with intermittent nights of undisturbed sleep. This pattern aimed at providing an ecologically highly valid experimental model of the typical sleep disturbances often reported in the general and patient populations. Unexpectedly, the experimental sleep disturbance model reduced several of the assessed proinflammatory markers, namely interleukin(IL)-6 production by monocytes and plasma levels of IL-6 and C-reactive protein (CRP), presumably due to intermittent increases in the counterinflammatory hormone cortisol. Striking sex differences were observed with females presenting a reduction in proinflammatory markers and males showing a predominantly proinflammatory response and reductions of cortisol levels. Our findings indicate that sleep disturbances causally dysregulate inflammatory pathways, with opposing effects in females and males. These results have the potential to advance our mechanistic understanding of the pronounced sexual dimorphism in the many diseases for which sleep disturbances are a risk factor.
... Cytokine storm is amplified by the key pro-inflammatory cytokine IL-6, whereas anti-inflammatory cytokines such as IL-10 control the pro-inflammatory response (Belaid et al., 2022). It is widely accepted that pro-and antiinflammatory mechanisms should be balanced while maintaining an adequate inflammatory response for pathogen clearance (Cicchese et al., 2018). Therefore, we argue that deciphering the balance of pro-and anti-inflammatory status in COVID-19 patients is a prerequisite for the development of efficient therapeutics and outcome-prediction tools. ...
Article
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The severity of COVID-19 is largely determined by the inflammatory response, a” Cytokine storm,” that involves both pro- and anti-inflammatory cytokines. In the current study we investigated the balance of pro- and anti-inflammatory status as represented by the levels of IL-6/IL-10 in severe to critical COVID-19 patients. 66 confirmed COVID-19 patients admitted to the ICU were categorized into groups according to the mortality and respiratory failure. Data were collected retrospectively in ICU, including a peripheral immune cells and infection-related biomarker CRP. The measurements of cytokine levels were performed by Immulite analyzer for IL-6 and ELISA sandwich for IL-10. In addition, longitudinal measurement of IL-6 was performed during 5 days post admission. Longitudinal assays showed that IL-6 was sustained at a medium level within 5 days post admission in severe cases who survived or not requiring mechanical ventilation, whereas it was sustained at high levels throughout the disease course in either deceased cases or who developed respiratory failure. The ratio of IL-6/lymphocytes was positively correlated with the risk of mortality, while IL-10/lymphocytes ratio could predict respiratory failure in ICU. IL-6/IL-10 profiling revealed that deceased patients have different magnitudes of both IL-6 and IL-10 cytokine release. Notably, excessive levels of IL-6 concomitant with high levels of IL-10 were more common in diseased COVID-19 patients. Taking into account the IL-6/IL-10 profiling may help clinicians to identify the right time of anti-inflammation treatment and select patients who will respond to anti-cytokine therapies and maintain an adequate inflammatory response for SARS-CoV-2 clearance
... The precise regulation of the onset, duration, and resolution of inflammation reflects responses to distinct signaling molecules produced at specific times. 1 Dysregulation of these processes underpins the pathology of numerous prevalent diseases. 2 Lipoxins (LXs) make up a class of endogenously generated eicosanoids typically generated through transcellular metabolism at a site of inflammation. ...
Article
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Lipoxins are important drivers of inflammation resolution, suggesting a potential therapeutic benefit. Bicyclo[1.1.1]pentanes (BCPs) are potential isosteric replacements for arenes and/or alkyl groups within drug candidates. We carried out an asymmetric synthesis of four BCP-containing synthetic lipoxin A4 mimetics (BCP-sLXms) in which the key steps were a Suzuki coupling, an asymmetric ketone reduction, and a triethylborane-initiated radical bicyclopentylation. These mimetics were screened for their impact on inflammatory responses, and one imidazolo-BCP-sLXm (6a) was found to possess high anti-inflammatory activity.
... The immune mediated liver pathology after virus infection could be limited or overt depending on many factors such as; genetic predisposition factors, the age of the host upon infection, the dose and route of infection [15]. Furthermore, the balance between the immunity and immunopathology is further determined by the levels of proinflammatory and anti-inflammatory factors [16]. The state in which the proinflammatory factors outpace the anti-inflammatory, viral clearance ,and tissue damage ensued [15]. ...
Article
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In the context of chronic viral infections, the hepatic microenvironment dictates the outcome of the disease by influencing propagation of virus and regulation of cytotoxic CD8 + T cell response. Nevertheless, such regulation could be beneficial as it resolves the disease or could be detrimental as it causes liver pathological consequences. Liver pathology is a hallmark of chronic viral infection in both human and murine models. Such models show viral infection of hepatocytes and subsequent direct hepatic damage. Other compelling studies showed that liver injury was a consequence of overshooting CD8 + T cells response in experimental mice, so-called immune-mediated liver pathology. This review highlights the viral-induced immune mediated aspects of liver pathology based on the lymphocytic choriomeningitis virus (LCMV) and Hepatitis virus settings.
... The extent of host susceptibility to M.tb infection correlates with the dynamics of pro-and anti-inflammatory responses, which are critical for T helper cell differentiation 33,57 . It is well established that a defect in Th1 immune responses leads to increased susceptibility to M.tb infection 26 . ...
Article
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Directly Observed Treatment Short-course (DOTs), is an effective and widely recommended treatment for tuberculosis (TB). The antibiotics used in DOTs, are immunotoxic and impair effector T cells, increasing the risk of re-infections and reactivation. Multiple reports suggest that addition of immune-modulators along with antibiotics improves the effectiveness of TB treatment. Therefore, drugs with both antimicrobial and immunomodulatory properties are desirable. N¹-(Adamantan-2-yl)-N²-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]ethane-1,2-diamine (SQ109) is an asymmetric diamine derivative of adamantane, that targets Mycobacterial membrane protein Large 3 (MmpL3). SQ109 dissipates the transmembrane electrochemical proton-gradient necessary for cell-wall biosynthesis and bacterial activity. Here, we examined the effects of SQ109 on host-immune responses using a murine TB model. Our results suggest the pro-inflammatory nature of SQ109, which instigates M1-macrophage polarization and induces protective pro-inflammatory cytokines through the p38-MAPK pathway. SQ109 also promotes Th1 and Th17-immune responses that inhibit the bacillary burden in a murine model of TB. These findings put forth SQ109 as a potential-adjunct to TB antibiotic therapy.
... Elevated Type 2 immunity has also been assumed to play an important function in susceptibility to TB infection (Deretic and Levine, 2009) and both IL-4 and IL-13 cytokines are shown to regulate Th1 mediated immune responses and to drive inappropriate alternate macrophage activation (Rook, 2007;Liu and Modlin, 2008;Deretic and Levine, 2009). Increased type 1 cytokines could possibly induce or extend the underlying immune-mediated pathology against TB infection (Cicchese et al., 2018;Stek et al., 2018). Our data show that Type 1 and Type 2 cytokine plasma levels were significantly reduced upon supplementation of high dose rifampicin indicating that the pro-inflammatory cytokine milieu, disease severity, and pathogenesis could potentially be attenuated upon treatment with high dose rifampicin. ...
Article
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High-dose rifampicin (HDR) is now undergoing clinical trials to improve the efficacy of anti-tuberculosis treatment (ATT). However, the influence of HDR in the modulation of different cytokines, chemokines/growth factors, microbial translocation markers (MTMs), and acute-phase proteins (APPs) in pulmonary tuberculosis (PTB) is not well known. PTB individuals were separated into three different arms (R10, R25, and R35) based on their rifampicin dosage. We examined the circulating levels of Type 1, Type 2, pro-inflammatory/regulatory cytokines, chemokines/growth factors, MTMs, and APPs at baseline and after completion of the second month of ATT by ELISA. The baseline levels of cytokines, chemokines/growth factors, MTMs, and APPs did not (except IL-5, IL-6, IL-17A, MCP-1, MIP-1β, GCSF, SAA, ⍺2 MG, Hp) significantly differ between the study individuals. However, at the second month, the plasma levels of Type 1 (TNFα and IFNγ), Type 2 (IL-4, IL-5, and IL-13), pro-inflammatory/regulatory cytokines (IL-6, IL-17A, IL-10, and GMCSF), and APPs were significantly decreased in R35 regimen- compared to R25 and/or R10 regimen-treated PTB individuals. In contrast, the plasma levels of IL-2, IL-8, MCP-1, MIP-1β, GSF, and MTMs were significantly increased in the R35 regimen compared to R25 and/or R10 regimen-treated PTB individuals. Overall, our data reveal that HDR could potentially be beneficial for host immunity by altering different immune and inflammatory markers.
... In addition to oxidative stress, the disruption of the balance between pro-inflammatory and anti-inflammatory molecules occurring during an inflammation causes many pathologies [98]. The antioxidant and anti-inflammatory activities of EVOO polyphenols are essentially related to their ability to attenuate reactive oxygen species (ROS), destroy carcinogenic metabolites, and act negatively on the inflammatory processes. ...
Article
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Much research has been conducted to reveal the functional properties of extra virgin olive oil polyphenols on human health once EVOO is consumed regularly as part of a balanced diet, as in the Mediterranean lifestyle. Despite the huge variety of research conducted, only one effect of EVOO polyphenols has been formally approved by EFSA as a health claim. This is probably because EFSA’s scientific opinion is entrusted to scientific expertise about food and medical sciences, which adopt very different investigative methods and experimental languages, generating a gap in the scientific communication that is essential for the enhancement of the potentially useful effects of EVOO polyphenols on health. Through the model of the Tower of Babel, we propose a challenge for science communication, capable of disrupting the barriers between different scientific areas and building bridges through transparent data analysis from the different investigative methodologies at each stage of health benefits assessment. The goal of this work is the strategic, distinctive, and cost-effective integration of interdisciplinary experiences and technologies into a highly harmonious workflow, organized to build a factual understanding that translates, because of trade, into health benefits for buyers, promoting EVOOs as having certified health benefits, not just as condiments.
... IL-10 is a key cytokine of immune regulation and has anti-inflammatory effects [26]. Although the exact role of IL-10 (and IL-10 family cytokines) is not clear yet [27], a role of immune regulation and the relevance of inflammatory as well as anti-inflammatory mechanisms in tuberculosis is well established [28]. Here, we found that IL-6/IL-10 ratios were optimal for discrimination between TB-Pb and TB-Sp patients. ...
Article
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Background Mycobacterium (M.) tuberculosis -caused immunopathology is characterized by aberrant expression of plasma cytokines in human tuberculosis. Disease severity and long-term anti-mycobacterial treatment are potentially influenced by immunopathology and normalization of plasma cytokine levels during therapy may indicate treatment efficacy and recovery. Study design and methods In this study, we analyzed the concentrations of selected plasma cytokines (i.e., IL-6, IP-10, IL-10, IL-22, IFNγ, GM-CSF, IL-8) and M. tuberculosis sputum burden in patients with tuberculosis ( n = 76). Cytokine levels were compared to healthy contacts ( n = 40) and changes under treatment were monitored (i.e., 6 and 16 weeks after treatment start). According to differences in M. tuberculosis sputum burden and conversion, tuberculosis patients were classified as paucibacillary as well as ‘rapid’ or ‘slow’ treatment responders. A subgroup of tuberculosis patients had fatal disease courses. Results Six of seven cytokines were significantly higher in tuberculosis patients as compared to contacts and four of these (i.e., IL-6, IP-10, IL-10, and IL-22) were detectable in the majority of tuberculosis patients. IL-6 showed the strongest discriminating capacity for tuberculosis disease and in combination with IL-10 concentrations efficiently classified paucibacillary tuberculosis cases as well as those with fatal disease outcome. In addition, IL-6 and IP-10 levels decreased significantly after 6 weeks of treatment and analyses of subgroups with differential treatment response showed delayed decline of IL-6 levels in slow treatment responders. Conclusions Combinations of different plasma cytokine (namely, IL-6, IL-10, and IP-10) efficiently classified tuberculosis patients with differential mycobacterial burden and especially IL-6 qualified as a biomarker candidate for early treatment response.
... In our study, maternal diet influenced the production of the proinflammatory cytokines TNF-α and IL-6 in the testis, demonstrating that an inflammatory response has been programmed. Nevertheless, an adequate and dynamic balance between pro-and anti-inflammatory mediators must exist and evolve over time to achieve control of the cause of inflammation without inducing tissue damage (Cicchese et al., 2018). IL-10 is an anti-inflammatory cytokine that plays a counter-regulatory role in the immune response to antigens, being produced in response to proinflammatory signals to prevent excessive inflammation (Rutz and Ouyang, 2016). ...
Article
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Parental nutrition can impact the health of future generations, programming the offspring for the development of diseases. The developing germ cells of the offspring could be damaged by the maternal or the paternal environment. The germ cells in development and their function could be affected by nutritional adversity and therefore, harm the health of subsequent generations. The paternal or maternal intake of high-fat diets has been shown to affect the reproductive health of male offspring, leading to imbalance in hypothalamic-pituitary-gonadal axis, testicular oxidative stress, low testosterone production, and changes in sperm count, viability, motility, and morphology. There is a need for studies that address the combined effects of diets with a high-fat and high-sugar (H) content by both progenitors on male reproduction. In this context, our study evaluated epigenetic parameters and the inflammatory response that could be associated to oxidative stress in testis and epididymis of adult offspring. 90 days-old male rats were divided according to the combination of the parental diet: CD (control paternal and maternal diet), HP (H paternal diet and control maternal diet), HM (H maternal diet and control paternal diet) and HPM (H paternal and maternal diet).We evaluated serum levels of testosterone and FSH; testicular gene expression of steroidogenic enzymes Star and Hsd17b3 and epigenetic markers Dnmt1, Dnmt3a, Dnmt3b, and Mecp2; testicular and epididymal levels of TNF-α, IL-6, IL-10, and IL-1β; testicular and epididymal activity of SOD, CAT, and GST; the oxidative markers MDA and CP; the daily sperm production, sperm transit time, and sperm morphology. Testicular epigenetic parameter, inflammatory response, oxidative balance, and daily sperm production of the offspring were affected by the maternal diet; paternal diet influenced serum testosterone levels, and lower daily sperm production was exacerbated by the interaction effect of both parental intake of high-fat high-sugar diet in the testis. There was isolated maternal and paternal effect in the antioxidant enzyme activity in the cauda epididymis, and an interaction effect of both parents in protein oxidative marker. Maternal effect could also be observed in cytokine production of cauda epididymis, and no morphological effects were observed in the sperm. The potential programming effects of isolated or combined intake of a high-fat high-sugar diet by the progenitors could be observed at a molecular level in the reproductive health of male offspring in early adulthood.
... Cytokine levels in the plasma are generally low, and a dynamic balance exists between pro-inflammatory and antiinflammatory factors. However, the balance could be broken by inflammation, oxidative stress, or cell injury during the disease process (71,72). The peripheral blood monocyte/macrophage cells from asymptomatic patients and patients with AMN and CLAD were all observed to have pro-inflammatory skewing (52,55). ...
Article
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X-linked adrenoleukodystrophy (X-ALD) is an inherited disease caused by a mutation in the ABCD1 gene encoding a peroxisomal transmembrane protein. It is characterized by the accumulation of very-long-chain fatty acids (VLCFAs) in body fluids and tissues, leading to progressive demyelination and adrenal insufficiency. ALD has various phenotypes, among which the most common and severe is childhood cerebral adrenoleukodystrophy (CCALD). The pathophysiological mechanisms of ALD remain unclear, but some in vitro/in vivo research showed that VLCFA could induce oxidative stress and inflammation, leading to damage. In addition, the evidence that oxidative stress and inflammation are increased in patients with X-ALD also proves that it is a potential mechanism of brain and adrenal damage. Therefore, normalizing the redox balance becomes a critical therapeutic target. This study focuses on the possible predictors of the severity and progression of X-ALD, the potential mechanisms of pathogenesis, and the promising targeted drugs involved in oxidative stress and inflammation.
... In cancer, cytokines are the critical mediators for development. In the cancer population, an imbalance between pro-inflammatory and anti-inflammatory mechanisms is seen (Cicchese et al. 2018). Cytokines like TNF-α is crucial for tumor progression as it provides the suitable environment for tumor growth, angiogenesis, and genomic instability. ...
Chapter
Breast cancer is the most frequently diagnosed and leading cancer with the highest morbidity worldwide in women. In the past few decades, researchers have applied so many strategies for treating and preventing breast cancer. Here, we will discuss a different critical aspect of tumor hypoxia, which occurs due to an imbalance between cellular oxygen and its supply to the cells. We have subsequently proposed that hypoxia-inducible factor prolyl hydroxylase has a crucial role in lipid peroxidation-mediated protection in breast cancer cells. Reactive oxygen species have a vital role in influencing breast cancer microenvironment, angiogenesis, metastasis, and survival in a concentration-dependent manner. Reactive oxygen species promote cell growth at low concentrations by activating MAPK/ERK1/2, p38, JNK, PI3K/AKT, NF-κB, MMPs, and VEGF. Still, at high concentrations, reactive oxygen species triggered the process of cell apoptosis. This chapter describes the metabolic adaptation, epigenetics, and glycolytic shift of the breast cancer cells. The lipid peroxidation method of free radical generation and the effect of reactive oxygen species in angiogenesis and apoptosis are also discussed. The targeted therapies of hypoxia like hypoxia prodrugs, gene therapy, and modulation of prolyl hydroxylase are the future targets for breast cancer treatment. Keywords Reactive oxygen species Breast cancer Hypoxia Prolyl hydroxylase Free radical Tumor microenvironment Glycolysis PUFA
... Importantly, the initial interaction between Mtb and macrophages determines whether the immune response eliminates the bacilli or if Mtb establishes an asymptomatic infection or active disease [88,89]. PRR signaling through nuclear factor-κB (NF-κB) and JNK/p38 mitogen-activated protein kinase (MAPK) regulates expression of proteins related to inflammatory response and resistance to infection, including pro-and anti-inflammatory cytokines and chemokines [90,91], enzymes whose products have antimicrobial activities, such as nitric oxide synthase 2 and phagocyte oxidase [92,93], proteins with regulatory activities such as heme oxygenase [94], or cell-autonomous antimycobacterial pathways such as autophagy [55,57], and proteins that promote Mtb-containing phagosome maturation [95]. apoptosis is dependent on its RING domain, suggesting that TRIM27 acts in a E3 ubiquitin ligase activity-dependent manner [32] (Figure 1). ...
Article
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Infection with Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), remains a significant global epidemic. Host resistance to Mtb depends on both adaptive and innate immunity mechanisms, including development of antigen-specific CD4 and CD8 T cells, production of inflammatory cytokines, bacterial phagocytosis and destruction within phagolysosomes, host cell apoptosis, and autophagy. A key regulatory mechanism in innate immunity is the attachment of the small protein ubiquitin to protein and lipid targets by the enzymatic activity of ubiquitin ligases. Here, we summarize the latest advances on the role of ubiquitination and ubiquitin ligases in host immunity against Mtb, with a focus on innate immunity signaling, inflammation, and antimicrobial autophagy. Understanding how ubiquitin ligases mediate immunity to Mtb, and the specific substrates of distinct ubiquitin ligases in the context of Mtb infection, could facilitate development of new host-directed antimicrobials.
... The results of logistic regression analysis and ROC curve analysis showed that the FRI risk predictor constructed based on five variables including NLR and MLR had a high diagnostic value for FRI in tibia fracture patients. During infection in patients with tibia FRI, the immune system produces an inflammatory response to neutralize or kill pathogens, maintaining a trade-off between clearing path-ogens and limiting damage to host tissues, and eventually leading to recovery or tissue healing [30]. Changes in the content of immune cells, including neutrophils, lymphocytes, and monocytes, easily obtained from complete blood counts, can reflect the balance between the immune status of the body and the invasion status of pathogens to a certain extent. ...
Article
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Objective: The diagnostic value of neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) in predicting fracture-related infection (FRI) in tibia fracture patients remains to be explored. Methods: A retrospective controlled study was carried out with 170 tibia FRI patients and 162 control subjects. The following information was evaluated at admission: age, gender, clinical features, number of white blood cells (WBCs), neutrophils, lymphocytes, monocytes, red blood cells (RBCs), platelets, level of hemoglobin, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), as well as NLR, MLR, and PLR. Results: The number of lymphocytes, RBCs, and platelets in the FRI group was higher than those in the control group, while the number of neutrophils and ESR level was lower (P < 0.05). The level of NLR and MLR was significantly lower in patients with tibia FRI than in control subjects (P < 0.05). Both indicators were positively correlated with WBCs, CRP level, and ESR level (P < 0.001). The results of logistic regression analysis showed that five variables including NLR, MLR, platelets, fracture pattern (closed or open fracture), and site pattern (single or multiple site) were used to construct the FRI risk predictor. The ROC curve analysis result showed that FRI risk predictor yielded the highest AUC, with a sensitivity of 91.2% and a specificity of 90.1%, and made the distinction efficiently between tibia FRI patients and non-FRI patients. Conclusion: NLR and MLR were decreased in tibia FRI patients compared to non-FRI patients. Both indicators had a positive correlation with WBCs, CRP level, and ESR level. FRI risk predictor constructed based on five variables including NLR and MLR had a high diagnostic value for tibia FRI.
... Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is still a serious disease that results in significant morbidity and mortality worldwide in humans and animals (Cicchese et al., 2018). Over thousands of years of co-existence, Mtb has evolved multiple strategies to evade control by the host. ...
Article
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Tumor necrosis factor alpha (TNF-α) is a crucial factor in the control of Mycobacterium tuberculosis (Mtb) infection. Pathogenic mycobacteria can inhibit and/or regulate host cell TNF-α production in a variety of ways to evade antituberculosis (anti-TB) immunity as well as facilitate immune escape. However, the mechanisms by which TNF-α expression in host cells is modulated to the benefit of mycobacteria is still an interesting topic and needs further study. Here, we report that macrophages infected with Mycobacterium marinum (Mm)—a close relative of Mtb—upregulated the expression of E3 ubiquitin ligase FBXW7. Specific silencing FBXW7 with small interfering RNA (siRNA) significantly elevates TNF-α expression and eventually promotes the elimination of intracellular bacteria. In turn, overexpression of FBXW7 in Raw264.7 macrophages markedly decreased TNF-α production. Furthermore, partial inhibition of FBXW7 in an Mm-infected murine model significantly reduced TNF-α tissue content, alleviated tissue damage as well as reduced the bacterial load of mouse tails. Finally, FBXW7 could decrease TNF-α in a K63-linked ubiquitin signaling dependent manner. Taken together, our study uncovered a previously unknown role of FBXW7 in regulating TNF-α dynamics during mycobacterial infection, which provides new insights into understanding the role of FBXW7 in anti-tuberculosis immunity and its related clinical significance.
Article
The coastal aquaculture is characterized with environmental salinity fluctuation, and the effects of salinity stress on the immunity of cultured fish are needed to be further explored. Scatophagus argus is an important species in the wild fisheries and aquaculture industry, it would be of great value to reveal the impact of salinity change on the immune response in this species. Understanding the effects of salinity stress on immune response can provide valuable insights into salinity management in the aquacultural process. The head kidney, which is an organ unique for teleost fish, functions not only as a central immune organ but also as a crucial role in the stress response during which the secretion of immunoregulatory molecules i.e. cytokines is facilitated. In the present study, Individuals of S. argus acclimated to 3 different salinities [0‰ (FW), 10‰ (BW), and 25‰ (SW)] were injected intraperitoneally with A. hydrophila, and then monitored throughout one week. The effects of environmental salinity on the immune response in S. argus stimulated by A. hydrophila infection were investigated. mRNA expression profiles of cytokine genes IL-1β, IL-6, IL-10 and TNF-α in different salinity groups was quite different. mRNA expression of cytokine genes in BW group and SW group rose more quickly and significantly higher than FW group (p < 0.05) at early stages (6–24 hpi) after bacterial injection, and before 96 hpi, the highest value of cytokine expression at each time point was recorded in SW group. Immune parameters such as lysozyme level, complement C3 activity and IgM content in BW and FW groups were lower than SW group at each time point from 24 to 144 hpi after bacterial injection. In addition, leukocyte profiles in the head kidney and blood were also investigated. Although hypoosmotic acclimation could temporarily stimulate monocyte and neutrophil proliferation, it was observed that the number of monocytes, neutrophils and lymphocytes of the head kidney and blood in SW group increased more quickly than BW and FW groups after bacterial infection. Our results indicate that hypoosmotic stress due to the decrease of environmental salinity has suppressive immunoregulatory effects on the immune response of S. argus.
Article
The combination of natural resources with biologically active biocompatible ionic liquids (Bio-IL) is presented as a combinatorial approach for developing tools to manage inflammatory diseases. Innovative biomedical solutions were constructed combining silk fibroin (SF) and Ch[Gallate], a Bio-IL with antioxidant and anti-inflammatory features, as freeze-dried 3D-based sponges. An evaluation of the effect of the Ch[Gallate] concentration (≤3% w/v) on the SF/Ch[Gallate] sponges was studied. Structural changes observed on the sponges revealed that the Ch[Gallate] presence positively affected the β-sheet formation while not influencing the silk native structure, which was suggested by the FTIR and solid-state NMR results, respectively. Also, it was possible to modulate their mechanical properties, antioxidant activity and stability/degradation in an aqueous environment, by changing the Ch[Gallate] concentration. The architectures showed high water uptake ability and a weight loss that follows the controlled Ch[Gallate] release rate studied for 7 days. Furthermore, the sponges supported human adipose stem cells growth and proliferation, up to 7 days. TNF-α, IL-6 (pro-inflammatory) and IL-10 (anti-inflammatory) release quantification from a human monocyte cell line revealed a decrease in the pro-inflammatory cytokines concentrations in samples containing Ch[Gallate]. These outcomes encourage the use of the developed architectures as tissue engineering solutions, potentially targeting inflammation processes. Statement of Significance : Combining natural resources with active biocompatible ionic liquids (Bio-IL) is herein presented as a combinatorial approach for the development of tools to manage inflammatory diseases. We propose using silk fibroin (SF), a natural protein, with cholinium gallate, a Bio-IL, with antioxidant and anti-inflammatory properties, to construct 3D-porous sponges through a sustainable methodology. The morphological features, swelling, and stability of the architectures were controlled by Bio-IL content in the matrices. The sponges were able to support human adipose stem cells growth and proliferation, and their therapeutic effect was proved by the blockage of TNF-α from activated and differentiated THP-1 monocytes. We believe that these bio-friendly and bioactive SF/Bio-IL-based sponges are effective for targeting pathologies with associated inflammatory processes.
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Phenotypic variations in the retinal pigment epithelial (RPE) layer are often a predecessor and driver of ocular degenerative diseases, such as age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We previously identified the orphan nuclear receptor-related 1 (NURR1), from a nuclear receptor atlas of human RPE cells, as a candidate transcription factor potentially involved in AMD development and progression. In the present study we characterized the expression of NURR1 as a function of age in RPE cells harvested from human donor eyes and in donor tissue from AMD patients. Mechanistically, we found an age-dependent shift in NURR1 dimerization from NURR1-RXRα heterodimers toward NURR1-NURR1 homodimers in primary human RPE cells. Additionally, overexpression and activation of NURR1 attenuated TNF-α–induced epithelial-to-mesenchymal transition (EMT) and migration, and modulated EMT-associated gene and protein expression in human RPE cells independent of age. In vivo, oral administration of IP7e, a potent NURR1 activator, ameliorated EMT in an experimental model of wet AMD and improved retinal function in a mouse model that presents with dry AMD features, impacting AMD phenotype, structure, and function of RPE cells, inhibiting accumulation of immune cells, and diminishing lipid accumulation. These results provide insight into the mechanisms of action of NURR1 in the aging eye, and demonstrate that the relative expression levels and activity of NURR1 is critical for both physiological and pathological functions of human RPE cells through RXRα-dependent regulation, and that targeting NURR1 may have therapeutic potential for AMD by modulating EMT, inflammation, and lipid homeostasis.
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Background Mycobacterium tuberculosis (TB) remains a disease of global health concern and a leading cause of mortality arising from an infectious agent. Protective immunity to TB remains unclear. Suppressor of cytokine signaling-3 (SOCS3) and signal transduction and activator of transcription-3 (STAT3) genes have shown potential to influence innate immunity. We, therefore, explored the expression of SOCS3 and STAT3 and their implications on the innate immunity in TB patients and their healthy close contacts. Methods We recruited 72 TB patients and 62 healthy contacts from a high TB and HIV endemic setting (Lusaka, Zambia). We used RT-PCRT and flow cytometry to quantify the expression of SOCS, STAT3 and cytokines respectively. Data was analysed Stata version 14.0 and figures were developed in GraphPad prism version 9.1.0 (221). Assessment for associations for categorical and continuous variables was analysed using the Chi-square test and Mann-Whitney test respectively. Spearman’s rank correlation was used to evaluate the relationship between SOCS3 and IL-6. A p -value < 0.05 was considered statistically significant. Results Healthy contacts markedly expressed SOCS3 in both unstimulated and stimulated whole blood in comparison to TB patients ( p <0.0001). STAT3 was elevated in TB patients in TB patients in stimulated blood only. IL-6 ( P = < 0.0001) and IL-10 ( P = <0.0001), were significantly expressed in Healthy contacts in comparison to TB patients. TNF-α ( p = 0.044) were markedly elevated in TB patients in comparison to healthy contacts. IL-6 and SOCS3 correlated significantly in healthy contacts only (r = 0.429, p = 0.02). Conclusions Both SOCS3 and STAT3 are genes of importance in mounting protective innate immunity against TB. We propose that SOCS3 stimulation and inhibition of STAT3 as possible approaches in gene therapy and vaccine development for TB.
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The immune system is an extremely complex biological network that plays a crucial role in the hemostasis of periapical tissue, pathogenesis of apical periodontitis (AP) as well as periapical tissue healing. The successful elimination of microbial infections remains a significant challenge, mostly due to the ever-growing development of antimicrobial-resistant pathogens. The bacterial endurance in the root canal system contributes to features ranging from altered post-treatment healing to exacerbation of chronic periradicular immune response, that compromise the outcome of endodontic treatment. A highly effective strategy for combating infectious diseases and the associated inflammation-mediated tissue damage is to modulate the host immune response in conjunction with antimicrobial therapy. There are several medications currently used in endodontic treatment, however, they suffer various levels of microbial resistance and do not deliver all the required characteristics to simultaneously address both intracanal bacteria and periapical inflammation. Interaction of antimicrobial agents with the immune system can impact its function, leading to immune-suppressive or immune-stimulatory effects. The group of non-conventional antimicrobial medications, such as antimicrobial peptides, propolis, and nanomaterials, are agents that provide strong antimicrobial effectiveness and concomitant immunomodulatory and/or reparative effect, without any host tissue damages. Herein, we provide an overview of local immune modulation in AP and a comprehensive review of the immunomodulatory effect of antimicrobials intracanal medications applied in endodontics with specific emphasis on the antimicrobial nanomaterial-based approaches that provide immunomodulatory potential for successful clinical deployment in endodontics.
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Cognition is believed to be a product of human evolution, while schizophrenia is ascribed as the by-product with cognitive impairment as it's genetically mediated endophenotype. Genomic loci associated with these traits are enriched with recent evolutionary markers such as Human accelerated regions (HARs). HARs are markedly different in humans since their divergence with chimpanzees and mostly regulate gene expression by binding to transcription factors and/or modulating chromatin interactions. We hypothesize that variants within HARs may alter such functions and thus contribute to disease pathogenesis. 49 systematically prioritized variants from 2737 genome-wide HARs were genotyped in a north-Indian schizophrenia cohort (331 cases, 235 controls). Six variants were significantly associated with cognitive impairment in schizophrenia, thirteen with general cognition in healthy individuals. These variants were mapped to 122 genes; predicted to alter 79 transcription factors binding sites and overlapped with promoters, enhancers and/or repressors. These genes and TFs are implicated in neurocognitive phenotypes, autism, schizophrenia and bipolar disorders; a few are targets of common or repurposable antipsychotics suggesting their draggability; and enriched for immune response and brain developmental pathways. Immune response has been more strongly targeted by natural selection during human evolution and has a prominent role in neurodevelopment. Thus, its disruption may have deleterious consequences for neuronal and cognitive functions. Importantly, among the 15 associated SNPs, 12 showed association in several independent GWASs of different neurocognitive functions. Further analysis of HARs may be valuable to understand their role in cognition biology and identify improved therapeutics for schizophrenia.
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Tuberculosis (TB) caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb) is one of the most lethal infectious diseases in the world. Presently, Bacillus Calmette-Guerin, the vaccine approved for use against TB, does not offer complete protection against the disease, which necessitates the development of new therapeutics to treat this infection. Overexpression of transforming growth factor beta (TGF-β) is associated with pulmonary profibrotic changes. The inactive TGF-β secreted is activated through its cleavage and release by αv integrins. Integrin-mediated regulation of TGF-β is considered as a master switch in the profibrotic process and a potential therapeutic target. Thus, in this study, we sought to determine if treatment with a broad range antagonist of integrins, CWHM-12, has the potency to inhibit pulmonary fibrosis and enhance Mtb control in a highly susceptible mouse model of Mtb infection, namely the C3Heb/FeJ (FeJ). CWHM-12 treatment at the early stages of Mtb infection was efficacious in reducing disease severity and inflammation associated with decreased iNOS, MIP-2, and IL-10 production without degradation of collagen. This suggests a potential for CWHM-12 targeting of TGF-β to be explored as an adjunct therapeutic for early Mtb infection.
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Lipopolysaccharide (LPS) is the major component of the outer membrane of Gram-negative bacteria and is usually administrated to establish models of inflammation. Artesunate (ART), a water-soluble artemisinin derivative, displays multiple pharmacological actions against tumors, viral infections, and inflammation, and has been used as a therapeutic weapon against malaria. In this study, our aim was to evaluate whether ART pretreatment is capable of preventing inflammation induced by LPS. BALB/c mice were treated with 100 mg/kg of ART i.p. for 7 days followed by a single dose of LPS. ART pretreatment led to an improvement in clinical score, prevented alterations in biochemical markers, and reestablished the platelet counts. Flow cytometry analysis showed that ART protected the inflammation mainly by reducing the percentage of M1 macrophages while increasing M2 macrophages and a reestablishment of classical monocytes in the BM. In the spleen, ART pretreatment increased N2 neutrophils, myeloid-derived suppressor cells (MDSC), and regulatory T cells, the latter was also increased in peripheral blood. In addition, a marked decrease in inflammatory cytokines and chemokines was observed in the ART treated group. Our data suggest that ART prevents inflammation, reducing tissue damage and restoring homeostasis.
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This study aimed to investigate the effect of N6‐methyladenosine (m6A) modification in modulating inflammatory homeostasis of arsenic (As)‐induced skin lesions. Our bioinformatic analysis revealed abnormal expression of m6A RNA methylation regulators and cytokines in the arsenic‐exposed population. In human keratinocytes, arsenite increased the levels of m6A methylation by upregulating the RNA methyltransferase like 3 (METTL3), mediating the disordered secretion of indicators that reflect inflammatory homeostasis (IL‐6, IL‐17, and IL‐10). The indicators reflecting arsenic‐induced skin lesions (Krt1 and Krt10) were also significantly elevated, which contributed to the occurrence of skin lesions. Our results also confirmed the association between METTL3 with inflammatory homeostasis and arsenic‐induced skin lesions using arsenic‐exposed human skin samples. In the arsenic‐exposed group, the upregulation of METTL3 exacerbated the increase in cytokine levels (IL‐6, IL‐17, and IL‐10), which was associated with the upregulation of keratins (Krt1 and Krt10). In addition, significant correlations among these factors corroborate the theoretical links. Finally, alteration of the m6A levels via knockdown or enhancement of the METTL3 protein could antagonize or aggravate arsenite‐induced imbalanced inflammatory homeostasis and human keratinocyte damage in HaCaT cells. Collectively, our study reveals some evidence that regulation of m6A modification plays an important role in arsenic‐induced skin lesions, which provide a new perspective on the mechanism of arsenite‐induced imbalanced inflammatory homeostasis in the field of RNA epigenetics.
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Background: Gout is the most common form of inflammatory arthritis, with a prevalence of 2.49% in the United Kingdom. It is characterised by episodes of acute inflammation (flares) caused by shedding of monosodium urate (MSU) crystals that deposit within and around joints when serum urate (SU) increases above its solubilisation point. Despite the central role of hyperuricaemia in the pathogenesis of gout, not everyone with elevated SU develop symptomatic gout. The reasons underlying the transition from asymptomatic hyperuricaemia, with our without MSU crystal deposits, to symptomatic gout remain poorly understood. Objectives: (1) To explore expression of inflammasome and toll-like receptors (TLRs)-associated genes and cytokine levels in different stages of the pathogenesis of gout: normal SU, hyperuricaemia without MSU crystal deposits, hyperuricaemia with asymptomatic MSU crystal deposits, intercritical gout and gout flares. (2) To generate a polygenic risk score (PRS) to distinguish gout cases from controls regardless of SU. (3) To generate and validate a genome-wide association study (GWAS) of asymptomatic hyperuricaemia controls vs. gout cases. (4) To generate a PRS to distinguish gout cases from controls with asymptomatic hyperuricaemia. Methods: Gene expression and cytokine profiling: Participants recruited for three clinical studies conducted at the Department of Academic Rheumatology were classified according to their SU, presence of MSU crystals, and/or gout stage. A total of 108 were included in the gene expression analysis, which evaluated the relative expression of 86 genes associated to inflammasome and TLRs pathways, using the QIAGEN RT2 RNA PCR Arrays. 185 participants were included in the cytokine measurements, conducted using latex agglutination and Meso-Scale Discovery by Affinity Biomarkers Labs. mRNA and cytokine levels were compared among groups using the Kruskal-Wallis H Test with Bonferroni post-hoc for independent measurements, and Wilcoxon signed-rank rest or Friedman test with Bonferroni post-hoc for repeated measurements. P-values were corrected for multiple testing using a false discovery rate of 5%. GWAS and PRS studies: Phenotype and genotype data from participants of the UK Biobank resource were used to derive two cohorts: (1) gout cases vs. non-gout controls (regardless SU levels), and (2) gout cases vs. asymptomatic hyperuricaemia controls. The second cohort was divided into the discovery dataset (comprised by 70% of the original cohort) and the replication dataset (comprised by 30% of the original cohort). Genotype data was quality controlled using PLINK v1.9 to remove participants with non-European ethnicity, third degree relatives, sex mismatches, low call-rate and heterozygosity outliers, and markers deviating from Hardy-Weinberg equilibrium and high missingness. Discovery and replication association analyses for gout vs. asymptomatic hyperuricaemia were conducted in PLINK using an additive logistic regression, with age at recruitment, sex and the first 10 principal components as covariates. Genome-wide associations were annotated using FUMA-SNP2GENE resource. PRS for gout vs. controls were calculated with PRSice v2.0, using the GUGC GWAS summary statistics as the base dataset and the UK Biobank genotype data as the target dataset. PRS for gout vs. asymptomatic hyperuricaemia were generated using the discovery GWAS summary statistics as the base dataset and the replication cohort as the target dataset. Predictive ability of the PRS, the demographic and combined models were assessed using the area under the receiving operating characteristic curve (AUROC). Results: Gene expression profiling: BIRC2, CD40LG, CXCL1, IL-1β, MEFV, NLRP12, PANX1, TNFSF14, TXNIP and XIAP showed a significant upregulation in participants with hyperuricaemia with asymptomatic MSU crystal deposits, compared to participants with normouricaemia. CFLAR, NAIP, NFBIA, NLRC4, NLRP6 and TLR2 were downregulated in participants during the intercritical stage, compared to the gout flare; however, these differences were not significant after correcting for multiple testing. When these 16 genes were compared among the whole spectrum of normouricaemia to acute gout, CD40LG, PANX1 and TNFSF14 showed a downregulation in participants with acute gout, compared to the groups of participants with asymptomatic hyperuricaemia. Cytokine profiling: In the comparison of intercritical gout vs. gout flare, the levels of VEGF-α and hsCRP showed significant differences. Cytokine levels did not show significant differences among participants with normouricaemia, hyperuricaemia without MSU crystals and hyperuricaemia with asymptomatic deposits of MSU crystals. When cytokines were compared among all groups, GRO-α, IL-1β, IL-6, IL-8, IP-10, MCP-1, TNF-α and hsCRP were greater in the intercritical gout group, compared to the normouricaemia and asymptomatic hyperuricaemia groups. PRS for gout: The best-fit PRS was generated from 10 SNPs, and showed a significant association with gout. The mean PRS for gout cases and controls were significantly different (0.016 compared to 0.0019, respectively). The predictive ability of the PRS alone was of 62% that increased to a 75% when added to the demographics model. GWAS and PRS for gout vs. asymptomatic hyperuricaemia: The GWAS revealed 13 independent SNPs located in or near ABCG2, SLC2A9, SLC22A11, GCKR, MEPE, ADH1B, and the non-coding regions PPM1K-DT and LOC105377323 These loci associated with the transition from asymptomatic hyperuricaemia to gout, and replicated successfully. The PRS generated to distinguish gout from asymptomatic hyperuricaemia was generated from association data of 17 SNPs and gave a predictive ability of 58.2% and 69.2% when combined with the demographics model. Conclusions: Inflammasome-associated gene expression and cytokine measurements suggest the activation of immune mechanisms in people with asymptomatic deposition of MSU crystals and subclinical systemic inflammation during intercritical gout. The GWAS findings revealed novel loci associated with gout, and confirms the importance of urate transporters and metabolic genes in SU variation and its central role in the pathogenesis of gout. Validation studies in independent datasets are required to confirm gene expression and genome-wide genotype results.
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Background: Transgenic animal production is an important means of livestock breeding and can be used to model pharmaceutical applications. Methods: In this study, to explore the biological activity of endogenously produced melatonin, Acetylserotonin-O-methyltransferase (ASMT)-overexpressed melatonin-enriched dairy goats were successfully generated through the use of pBC1-ASMT expression vector construction and prokaryotic embryo microinjection. Results: These transgenic goats have the same normal phenotype as the wild-type goats (WT). However, the melatonin levels in their blood and milk were significantly increased (p < 0.05). In addition, the quality of their milk was also improved, showing elevated protein content and a reduced somatic cell number compared to the WT goats. No significant changes were detected in the intestinal microbiota patterns between groups. When the animals were challenged by the intravenous injection of E. coli, the ASMT-overexpressed goats had a lower level of pro-inflammatory cytokines and higher anti-inflammatory cytokines compared to the WT goats. Metabolic analysis uncovered a unique arachidonic acid metabolism pattern in transgenic goats. Conclusions: The increased melatonin production due to ASMT overexpression in the transgenic goats may have contributed to their improved milk quality and enhanced the anti-inflammatory ability compared to the WT goats.
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The cold-inducible proteins (CIPs) are essential for post-transcriptional gene regulation playing diverse tissue-specific roles in maintaining normal cellular function and morphogenesis. The potential implications of CIPs in reproductive events raise questions about their role in the physiology of the bovine reproductive tract. However, the expression changes of CIPs during the bovine estrous cycle have not been studied so far. Here, we hypothesized that the bovine estrous cycle could affect the mRNA expression of the CIPs and other candidate transcripts in the reproductive tract. This study aimed to examine estrous cycle-dependent mRNA expression patterns in the bovine endometrium and ampulla of three of the major described CIPs (CIRBP, RBM3, SRSF5), a set of inflammatory cytokines (IL-10, IL-18, IL-1β), and other candidate genes (IL-10RA, IL-10RB, BCL2, NLRP3, STAT1, STAT3, STAT5A, STAT6). Endometrial and ampullar tissues were assessed by RT-qPCR. Additionally, the mRNA expression levels were correlated among them and with follicular progesterone and estradiol concentrations. The transcript levels of CIPs increased in the endometrium during stage III (Days 11–17) compared to stage I (Days 1–4) and IV (Days 18–20). In the ampulla, the mRNA expression of CIRBP increased during the late luteal phase (stage III), but no differences in the expression of other CIPs were observed. This study expands the current knowledge regarding mRNA expression in the endometrium and oviductal ampulla of cycling heifers, focusing mainly on the CIPs. A better understanding of the mechanisms within the uterus and oviduct during the estrous cycle is crucial to improving the fertility rate.
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Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (Mtb), is one of the world’s deadliest infectious diseases and remains a significant global health burden. TB disease and pathology can present clinically across a spectrum of outcomes, ranging from total sterilization of infection to active disease. Much remains unknown about the biology that drives an individual towards various clinical outcomes as it is challenging to experimentally address specific mechanisms driving clinical outcomes. Furthermore, it is unknown whether numbers of immune cells in the blood accurately reflect ongoing events during infection within human lungs. Herein, we utilize a systems biology approach by developing a whole-host model of the immune response to Mtb across multiple physiologic and time scales. This model, called HostSim, tracks events at the cellular, granuloma, organ, and host scale and represents the first whole-host, multi-scale model of the immune response following Mtb infection. We show that this model can capture various aspects of human and non-human primate TB disease and predict that biomarkers in the blood may only faithfully represent events in the lung at early time points after infection. We posit that HostSim, as a first step toward personalized digital twins in TB research, offers a powerful computational tool that can be used in concert with experimental approaches to understand and predict events about various aspects of TB disease and therapeutics.
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Multiple cytokines and inflammatory markers control TB infection. We aimed to investigate the changes in multiple cytokines and inflammatory markers in active TB patients following anti-TB drug therapy. Twenty-nine patients with active TB were recruited prospectively between December 2010 and July 2017. Blood samples were collected before (T0), after 2 months (T2), and at the end of anti-TB treatment (Tend). We measured the levels of Interferon (IFN)-γ, interleukin (IL)-2, IL-12, IL-10, IL-13 and tumor necrosis factor (TNF)-α in supernatants collected from the QuantiFERON-TB Gold In-Tube assay (QFT-GIT), as well as the WBC, neutrophil, platelet count and neutrophil to lymphocyte ratio (NLR) in whole blood. Compared with baseline levels, WBC, neutrophil, and platelet counts were significantly lower following treatment. In addition, the NLR after treatment significantly decreased compared with baseline, whereas the IL-2/IFN-γ ratio increased after treatment. In conclusion, the levels of IL-2/IFN-γ ratios in the supernatant and the NLR might be useful biomarkers to evaluate the effectiveness of drug therapy in active TB patients.
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Mycobacterium tuberculosis is the pathogenic bacterium that causes tuberculosis (TB), one of the most lethal infectious diseases in the world. The only vaccine against TB is minimally protective, and multi-drug resistant TB necessitates new therapeutics to treat infection. Developing new therapies requires a better understanding of the complex host immune response to infection, including dissecting the processes leading to formation of granulomas, the dense cellular lesions associated with TB. In this work, we pair experimental and computational modeling studies to explore cytokine regulation in the context of TB. We use our next-generation hybrid multi-scale model of granuloma formation (GranSim) to capture molecular, cellular, and tissue scale dynamics of granuloma formation. We identify TGF-β1 as a major inhibitor of cytotoxic T-cell effector function in granulomas. Deletion of TGF-β1 from the system results in improved bacterial clearance and lesion sterilization. We also identify a novel dichotomous regulation of cytotoxic T cells and macrophages by TGF-β1 and IL-10, respectively. These findings suggest that increasing cytotoxic T-cell effector functions may increase bacterial clearance in granulomas and highlight potential new therapeutic targets for treating TB.
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Granulomas are complex lung lesions that are the hallmark of tuberculosis (TB). Understanding antibiotic dynamics within lung granulomas will be vital to improving and shortening the long course of TB treatment. Three fluoroquinolones (FQs) are commonly prescribed as part of multi-drug resistant TB therapy: moxifloxacin (MXF), levofloxacin (LVX) or gatifloxacin (GFX). To date, insufficient data are available to support selection of one FQ over another, or to show that these drugs are clinically equivalent. To predict the efficacy of MXF, LVX and GFX at a single granuloma level, we integrate computational modeling with experimental datasets into a single mechanistic framework, GranSim. GranSim is a hybrid agent-based computational model that simulates granuloma formation and function, FQ plasma and tissue pharmacokinetics and pharmacodynamics and is based on extensive in vitro and in vivo data. We treat in silico granulomas with recommended daily doses of each FQ and compare efficacy by multiple metrics: bacterial load, sterilization rates, early bactericidal activity and efficacy under non-compliance and treatment interruption. GranSim reproduces in vivo plasma pharmacokinetics, spatial and temporal tissue pharmacokinetics and in vitro pharmacodynamics of these FQs. We predict that MXF kills intracellular bacteria more quickly than LVX and GFX due in part to a higher cellular accumulation ratio. We also show that all three FQs struggle to sterilize non-replicating bacteria residing in caseum. This is due to modest drug concentrations inside caseum and high inhibitory concentrations for this bacterial subpopulation. MXF and LVX have higher granuloma sterilization rates compared to GFX; and MXF performs better in a simulated non-compliance or treatment interruption scenario. We conclude that MXF has a small but potentially clinically significant advantage over LVX, as well as LVX over GFX. We illustrate how a systems pharmacology approach combining experimental and computational methods can guide antibiotic selection for TB.
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Infection by Leishmania protozoan parasites can cause a variety of disease outcomes in humans and other mammals, from single self-healing cutaneous lesions to a visceral dissemination of the parasite. The correlation between chronic lesions and ecto-nucleotidase enzymes activity on the surface of the parasite is addressed here using damage caused in epithelial cells by nitric oxide. In order to explore the role of purinergic metabolism in lesion formation and the outcome of the infection, we implemented a cellular automata/lattice gas model involving major immune characters (Th1 and Th2 cells, IFN-γ, IL-4, IL-12, adenosine−Ado−, NO) and parasite players for the dynamic analysis of the disease progress. The model were analyzed using partial ranking correlation coefficient (PRCC) to indicate the components that most influence the disease progression. Results show that low Ado inhibition rate over Th-cells is shared by L. major and L. braziliensis, while in L. amazonensis infection the Ado inhibition rate over Th-cells reaches 30%. IL-4 inhibition rate over Th-cell priming to Th1 independent of IL-12 are exclusive of L. major. The lesion size and progression showed agreement with published biological data and the model was able to simulate cutaneous leishmaniasis outcomes. The sensitivity analysis suggested that Ado inhibition rate over Th-cells followed by Leishmania survival probability were the most important characteristics of the process, with PRCC of 0.89 and 0.77 respectively. The simulations also showed a non-linear relationship between Ado inhibition rate over Th-cells and lesion size measured as number of dead epithelial cells. In conclusion, this model can be a useful tool for the quantitative understanding of the immune response in leishmaniasis.
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Clinical trials and practice have shown that ethambutol is an important component of the first line tuberculosis (TB) regime. This contrasts the drug's rather modest potency and lack of activity against non-growing persister mycobacteria. The standard plasma-based pharmacokinetic-pharmacodynamic profile of ethambutol suggests that the drug may be of limited clinical value. Here we hypothesized that this apparent contradiction may be explained by favorable penetration of the drug into TB lesions. First we utilized novel in vitro lesion pharmacokinetic assays and predicted good penetration of the drug into lesions. We then employed mass spectrometry imaging and laser capture microdissection coupled to liquid chromatography and tandem mass spectrometry (LCM/LCMS) to show that ethambutol indeed accumulates in diseased tissues and penetrates the major human-like lesion types represented in the rabbit model of TB disease with a lesion-to-plasma exposure ratio ranging from 9 to 12. In addition, ethambutol exhibits slow but sustained passive diffusion into caseum to reach concentrations markedly higher than measured in plasma at steady state. The results explain why ethambutol has retained its place in the first line regimen, validate our in vitro lesion penetration assays and demonstrate the critical importance of effective lesion penetration for anti-TB drugs. Our findings suggest that in vitro and in vivo lesion penetration evaluation should be included in TB drug discovery programs. Finally, this is the first time that LCM/LCMS is used to quantify a small molecule at high spatial resolution in infected tissues, a method that can easily be extended to other infectious diseases.
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Infection with M. tuberculosis remains one of the most common infections in the world. The outcome of the infection depends on host ability to mount effective protection and balance inflammatory responses. Neutrophils are innate immune cells implicated in both processes. Accordingly, during M. tuberculosis infection, they play a dual role. Particularly, they contribute to the generation of effector T cells, participate in the formation of granuloma, and are directly involved in tissue necrosis, destruction, and infection dissemination. Neutrophils have a high bactericidal potential. However, data on their ability to eliminate M. tuberculosis are controversial, and the results of neutrophil depletion experiments are not uniform. Thus, the overall roles of neutrophils during M. tuberculosis infection and factors that determine these roles are not fully understood. This review analyzes data on neutrophil defensive and pathological functions during tuberculosis and considers hypotheses explaining the dualism of neutrophils during M. tuberculosis infection and tuberculosis disease.
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Infection with Mycobacterium tuberculosis causes a spectrum of outcomes; the majority of individuals contain but do not eliminate the infection, while a small subset present with primary active tuberculosis (TB) disease. This variability in infection outcomes is recapitulated at the granuloma level within each host, such that some sites of infection can be fully cleared while others progress. Understanding the spectrum of TB outcomes requires new tools to deconstruct the mechanisms underlying differences in granuloma fate. Here, we use novel genome-encoded barcodes to uniquely tag individual M. tuberculosis bacilli, enabling us to quantitatively track the trajectory of each infecting bacterium in a macaque model of TB. We also introduce a robust bioinformatics pipeline capable of identifying and counting barcode sequences within complex mixtures and at various read depths. By coupling this tagging strategy with serial positron emission tomography coregistered with computed tomography (PET/CT) imaging of lung pathology in macaques, we define a lesional map of M. tuberculosis infection dynamics. We find that there is no significant infection bottleneck, but there are significant constraints on productive bacterial trafficking out of primary granulomas. Our findings validate our barcoding approach and demonstrate its utility in probing lesion-specific biology and dissemination. This novel technology has the potential to greatly enhance our understanding of local dynamics in tuberculosis.
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The penetration of antibiotics in necrotic tuberculosis lesions is heterogeneous and drug-specific, but the factors underlying such differential partitioning are unknown. We hypothesized that drug binding to macromolecules in necrotic foci (or caseum) prevents passive drug diffusion through avascular caseum, a critical site of infection. Using a caseum binding assay and MALDI mass spectrometry imaging of tuberculosis drugs, we showed that binding to caseum inversely correlates with passive diffusion into the necrotic core. We developed a high-throughput assay relying on rapid equilibrium dialysis and a caseum surrogate designed to mimic the composition of native caseum. A set of 279 compounds was profiled in this assay to generate a large data set and explore the physicochemical drivers of free diffusion into caseum. Principle component analysis and modeling of the data set delivered an in silico signature predictive of caseum binding, combining 69 molecular descriptors. Among the major positive drivers of binding were high lipophilicity and poor solubility. Determinants of molecular shape such as the number of rings, particularly aromatic rings, number of sp2 carbon counts, and volume-to-surface ratio negatively correlated with the free fraction, indicating that low-molecular-weight nonflat compounds are more likely to exhibit low caseum binding properties and diffuse effectively through caseum. To provide simple guidance in the property-based design of new compounds, a rule of thumb was derived whereby the sum of the hydrophobicity (clogP) and aromatic ring count is proportional to caseum binding. These tools can be used to ensure desirable lesion partitioning and guide the selection of optimal regimens against tuberculosis.
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