Theodore J. Kottom’s research while affiliated with Mayo Clinic and other places

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Publications (102)


Preclinical and Toxicology Assessment of ISFP10, an Inhibitor of Fungal Phosphoglucomutase (PGM)
  • Preprint

January 2025

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4 Reads

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Marc Bindzus

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Theodore J. Kottom

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Background and Objective Previously, the novel small molecule ISFP10 has been shown to inhibit fungal phosphoglucomutase (PGM) activity in Aspergillus fumigatus and Pneumocystis spp. With 50-fold selectivity over the human PGM molecule due to the presence of a unique yet conserved cysteine residue present in a number pathogenic fungal PGMs, use of this compound may provide a novel broad-spectrum approach to treating fungal infections. Accordingly, we sought to determine the tolerability in test animals receiving this compound, as well as the potential antifungal activity of ISFP10 on cultures of the common fungal pathogens Candida albicans and Candida glabrata . Methods C57BL6 mice received once daily intraperitoneal (IP) injections of 100 mL of vehicle control (DMSO) or ISFP10 at a concentration of 10 mg/kg. Body weights were recorded daily for 7 days of treatment. On the final day, mice were weighed and euthanized. Postmortem blood collection was conducted via cardiac puncture and distributed to EDTA and lithium heparin tubes for complete blood count (CBC) and comprehensive blood chemistry panels, respectively. Liver, kidney, and lung tissue were also harvested and placed in 10% formalin for H&E staining and blinded histopathologic scoring. Lung samples were further analyzed for proinflammatory cytokines using enzyme-linked immunosorbent assays (ELISA) and quantitative PCR (qPCR). Furthermore, ISPF10 was tested for antifungal activity via 8-hour growth curve analysis in a concentration-dependent fashion against Candida albicans and Candida glabrata . Results There was no significant difference in the daily or final body weights of the mice receiving 10 mg/kg of ISFP10 compared to those of the vehicle control group. Extracellular matrix (ECM) transcripts for IL-6 and TNFα were statistically similar via qPCR. ELISA results of proinflammatory cytokines for IL-6 was not significant whereas TNFα levels in lung tissue from the ISFP10 treatment group were significantly reduced, indicating a potential anti-inflammatory effect of ISFP10 at this dosage. Overall, blood chemistry and CBC analysis revealed no overall significant differences between the two groups, except for increased neutrophil counts and decreased potassium levels in samples collected from ISFP10 treated animals compared to the vehicle control group. These laboratory abnormalities were not of clinical significance to the test animals. Blinded histopathological examination revealed no abnormalities or evidence of critical organ toxicity from all groups. Inhibition of C. albicans and C. glabrata culture growth by ISFP10 was concentration-dependent in YPD liquid media containing the ISFP10 compared to vehicle control. Conclusions Our preliminary testing of ISFP10 revealed no inherent safety or toxicology concerns within the observed parameters. These data further support significant culture suppressive activity against C. albicans and C. glabrata . Taken together, these observations of ISFP10 further indicate that targeting PGM might be a novel and viable therapeutic strategy for serious fungal infections. Key points An inhibitor specific to fungal PGM enzymes, termed ISFP10, was generally well tolerated when administered via intraperitoneal (IP) injection in mice. ISFP10 displays antifungal activity in a concentration-dependent manner against C. albicans and C. glabrata .


Clec7a−/− Fcer1g−/− mice exhibit significantly increased organism burden during PCP. Card9−/−, Clec7a−/− Fcer1g−/−, and WT mice were immunosuppressed by the depletion of CD4 cells and subsequently inoculated with P. murina (Pm) organisms. (A) After 8 weeks, the Pm organism burden was determined by Pm 16S mitochondrial ribosomal DNA copy number and assessed using a standard curve. Data are derived from 7 to 10 mice per group ± SEM; *P < 0.05,**P < 0.01, ***P < 0.001, and ****P < 0.0001 comparing Pm burden in the Card9−/−, Clec7a−/− Fcer1g−/−, and WT mice and are representative of two separate experiments. (B) qPCR analysis of trophic-specific Sp RNA. (C) ELISA analysis of the major surface glycoprotein (Msg) from the respective infected lung tissues. (D) qPCR analysis of cyst-specific Gsc1 RNA. (E) ELISA analysis of the β−1,3 glucan content from the respective infected lung tissues.
Analysis of lung sections shows exuberant cyst forms in the Clec7a−/− Fcer1g−/− mice and less inflammation. After 8 weeks of infection, the lungs were fixed in 10% phosphate-buffered formalin, and 5 µm sections were obtained. Gomori Methenamine Silver stains (GMS) for P. murina (Pm) organisms were performed, demonstrating numerous more cyst life forms in the Clec7a−/− Fcer1g−/− mice lungs (A and B, panel 3) versus WT (A and B, panel 1) and Card9−/− lungs (A and B, panel 2). H&E staining showed the presence of substantially fewer lymphocytic aggregates in the Clec7a−/− Fcer1g−/−-infected PCP mouse lung (C and D, panel 3) compared with the other two mouse groups. As indicated, for original magnification, ×70, scale bars are 1,500 µm (A and C) and for original magnification ×400, scale bars are 25 µm (B and D). Quantification of H&E slides with a lung inflammation score (D). *P < 0.05, comparing Pm-infected WT, Card9−/−, and Clec7a−/− Fcer1g−/− mice. The data shown are derived from six animals and shown as mean ± SEM per group.
Inflammatory cytokines are significantly reduced in the lungs of Clec7a−/− Fcer1g−/− PCP-induced mice in absence. WT, Clec7a−/− Fcer1g−/−, or Card9−/− mice were infected with Pm. After 8 weeks of infection, the lungs were harvested, and protein lysates were obtained. Levels of the indicated inflammatory cytokines were measured using ELISA. *P < 0.05, **P < 0.01, and ****P < 0.0001 comparing Pm infected WT vs Card9−/− and Clec7a−/− Fcer1g−/− mice, and the data shown are derived from n > 9 animals and shown as mean ± SEM per group and are representative of two separate animal runs.
Clec7a−/− Fcer1g−/− mice are significantly deficient in their ability to clear fungal organisms in an intact T-cell immunocompetent PCP model. WT, Clec7a−/− Fcer1g−/−, or Card9−/− immunocompetent mice were infected with Pm. After 30 (A) or 60 (B) days of infection, the lungs were harvested, and organism burden was determined by 16S mitochondrial ribosomal DNA–targeted qPCR, and the copy number was assessed using a standard curve. Data in (A-B) are derived from n > 6 animals per group and shown as mean ± SEM; *P < 0.05.
Proinflammatory cytokines are significantly reduced in alveolar macrophage from Clec7a−/− Fcer1g−/− mice. AMs were stimulated with Pm homogenate for 24 h. After stimulation, macrophage supernatants were collected and analyzed using ELISA for protein levels of (A) TNF-α and (B) IL-6, respectively. Data shown are integrated means ± the SEM of four independent experiments: *P < 0.05, ***P < 0.001.

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The importance of Fcγ and C-type lectin receptors in host immune responses during Pneumocystis pneumonia
  • Article
  • Full-text available

December 2024

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23 Reads

Pneumocystis jirovecii pneumonia (PJP) remains a significant cause of morbidity and mortality during AIDS. In AIDS, the absence of CD4 immunity results in exuberant and often fatal PJP. In addition, organism clearance requires a balanced macrophage response since excessive inflammation promotes lung injury and respiratory failure. Corticosteroids given in addition to antibiotics significantly improve outcomes during PJP. However, concerns exist that corticosteroids further suppress immunity and increase co-infections. New strategies to promote killing and clearance of Pneumocystis while balancing lung inflammation are required. Prior studies have shown that innate immunity to Pneumocystis is mediated by C-type lectin receptors (CLRs) on macrophages and involves downstream CARD9 activation. CARD9 can be targeted by a novel specific small molecule inhibitor (BRD5529) that significantly reduces inflammatory signaling by macrophages. CARD9 serves as the central intracellular molecule through which Dectin-1, Dectin-2, Mincle, and other CLRs signal. Dectin-1 CLR is activated through its own intracytoplasmic domain, whereas other innate CLRs (e.g., Dectin-2 and Mincle) require interactions with a common Fc-gamma receptor (FcγR) accessory chain to mediate responses. We now observe that mice double deficient in both Dectin-1 and Fcer1g (which lack the FcγR gamma chain) exhibit markedly reduced organism clearance compared with Card9−/− infected animals. These mice also possess deficiencies in immunoglobulin (Ig) Fc receptors directly mediating antibody responses, further implicating altered humoral responses in Pneumocystis killing. We further demonstrate in the Pneumocystis pneumonia (PCP) mouse model that BRD5529 administration successfully suppresses inflammatory cytokines. Our data support that innate immune responses through the CLR-CARD9 axis and humoral response act together to mediate effective responses resulting in optimal organism killing and generation of host inflammatory responses. Furthermore, host lung inflammation during PCP may be successfully reduced with a novel CARD9 small molecule inhibitor. IMPORTANCE Pneumocystis pneumonia (PCP) causes severe respiratory impairment in hosts with suppressed immunity, particularly those with CD4 deficiencies, such as HIV. In addition to lymphocytic immunity, both innate and humoral immunities also participate in host defense against Pneumocystis. In the current studies, we defined the relative roles of CLR receptor-mediated inflammation, as well as FcgR-related inflammation and clearance of Pneumocystis organisms. Our studies reveal important roles for CLR activities for inducing lung inflammation, which can be ameliorated with a novel small molecule inhibitor of the CARD9 adaptor protein that is necessary for CLR signaling. In contrast, FcgR has a dominant role in organism clearance, underscoring an integral role of humoral responses for the elimination of this infection.

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Preclinical and Toxicology Assessment of ALW-II-41-27, an Inhibitor of the Eph Receptor A2 (EphA2)

August 2024

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42 Reads

Drugs in R & D

The EphA2 receptor inhibitor ALW-II-41-27 has proven to be an effective in vitro antagonist of Pneumocystis β-glucan-induced proinflammatory signaling. This suggests its potential as a candidate for initial anti-inflammatory drug testing in the rodent model of Pneumocystis pneumonia (PCP). Initially, single-dose intraperitoneal (IP) injections of ALW-II-41-27 were administered at concentrations of 0, 10, 15, 20, and 30 mg/kg over a 24-h treatment period. Pharmacokinetics were assessed in plasma, bronchoalveolar lavage fluid (BALF), and epithelial lining fluid (ELF). Following these assessments, a final single mg/kg dosing was determined. Mice received daily IP injections of either vehicle or 20.0 mg/kg of ALW-II-41-27 for 10 days, with their weights recorded daily. On day 11, mice were weighed and euthanized. Lungs, liver, and kidneys were harvested for H&E staining and pathology scoring. Lung samples were further analyzed for proinflammatory cytokines using enzyme-linked immunosorbent assay (ELISA) and extracellular matrix production using quantitative PCR (qPCR). Postmortem blood collection was conducted for complete blood count (CBC) blood chemistry analysis. Lastly, ALW-II-41-27 was administered to mice prior to fungal β-glucans challenge to determine in vivo effects on lung inflammation. This report describes the PK assessment of ALW-II-41-27 given via IP in C57BL/6 mice. After PK data were generated, we tested ALW-II-41-27 at 20 mg/kg IP in mice and noted no significant changes in daily or final weight gain. ELISA results of proinflammatory cytokines from lung tissues showed no major differences in the respective groups. qPCR analysis of extracellular matrix transcripts were statistically similar. Examination and pathology scoring of H&E slides from lung, liver, and kidney in all groups and subsequent pathology scoring showed no significant toxicity. Blood chemistry and CBC analyses revealed no major abnormalities. Additionally, administering ALW-II-41-27 before intratracheal inoculation of fungal β-glucans, known to induce a strong proinflammatory response in the lungs, significantly reduced lung tissue IL-1β levels. In our initial general safety and toxicology assessments, ALW-II-41-27 displayed no inherent safety concerns in the analyzed parameters. These data support broader in vivo testing of the inhibitor as a timed adjunct therapy to the deleterious proinflammatory host immune response often associated with anti-Pneumocystis therapy.


Fig. 1. (A) Percentage of respective yeast strain binding to CLR hFc-fusions. (B) Colony forming unit (CFU) counts of the respective bound/internalized yeast strains. Data analysis was initially first performed with ANOVA. If ANOVA indicated overall differences, subsequent group analysis was then performed by a two-sample unpaired Student t test for normally distributed variables. Error bars show SD from the mean. *P < 0.05, **P < 0.01, ns = non-significant.
Monosaccharide compositions and total carbohydrate by weight of the yeast cell wall pellet samples.
Metabolic modulation: Pneumocystis phosphoglucomutase is a target influencing host recognition

The Cell Surface

Herein, this manuscript explores the significance of the phosphoglucomutase (PGM) enzyme in Pneumocystis spp., focusing on its role in fungal surface mannoprotein formation. Through expression of the Pneumocystis murina Pmpgm2 in a Saccharomyces cerevisiae pgm2Δ strain, we demonstrate restoration of binding to the mannose receptor (MR) and macrophages to wildtype yeast levels in this complemented strain. Gas Chromatography-Mass Spectroscopy (GC-MS) confirmed reduced mannose content in the pgm2Δ yeast strain compared to the wild-type and complemented Pmpgm2 cDNA-expressing strains. This study underscores fungal PGM function in dolichol glucosyl phosphate biosynthesis, crucial for proper cell wall mannoprotein formation. Furthermore, highlighting the conservation of targetable cysteine residues across fungal pathogens, PGM inhibition maybe a potential therapeutic strategy against a broad spectrum of fungal infections.


The commensal fungus Wallemia mellicola enhances asthma in mice through Dectin-2

February 2024

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8 Reads

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2 Citations

Medical mycology: official publication of the International Society for Human and Animal Mycology

Overgrowth of the fungus Wallemia mellicola in the intestines of mice enhances the severity of asthma. Wallemia mellicola interacts with the immune system through Dectin-2 expressed on the surface of myeloid and intestinal epithelial cells. Using Dectin-2-deficient mice, we show that the interaction of W. mellicola with Dectin-2 is essential for the gut-lung pathways, enhancing the severity of asthma in mice with W. mellicola intestinal dysbiosis. These findings offer better insight into dysbiosis-associated inflammation and highlight the role pattern recognition receptors have in immune recognition of commensal fungi in the gut, leading to alterations in immune function in the lungs.


Characterization of the Pneumocystis jirovecii and Pneumocystis murina phosphoglucomutases (Pgm2s): a potential target for Pneumocystis therapy

January 2024

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76 Reads

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1 Citation

Pneumocystis cyst life forms contain abundant β-glucan carbohydrates, synthesized using β-1,3 and β-1,6 glucan synthase enzymes and the donor uridine diphosphate (UDP)-glucose. In yeast, phosphoglucomutase (PGM) plays a crucial role in carbohydrate metabolism by interconverting glucose 1-phosphate and glucose 6-phosphate, a vital step in UDP pools for β-glucan cell wall formation. This pathway has not yet been defined in Pneumocystis. Herein, we surveyed the Pneumocystis jirovecii and Pneumocystis murina genomes, which predicted a homolog of the Saccharomyces cerevisiae major PGM enzyme. Furthermore, we show that PjPgm2p and PmPgm2p function similarly to the yeast counterpart. When both Pneumocystis pgm2 homologs are heterologously expressed in S. cerevisiae pgm2Δ cells, both genes can restore growth and sedimentation rates to wild-type levels. Additionally, we demonstrate that yeast pgm2Δ cell lysates expressing the two Pneumocystis pgm2 transcripts individually can restore PGM activities significantly altered in the yeast pgm2Δ strain. The addition of lithium, a competitive inhibitor of yeast PGM activity, significantly reduces PGM activity. Next, we tested the effects of lithium on P. murina viability ex vivo and found the compound displays significant anti-Pneumocystis activity. Finally, we demonstrate that a para-aryl derivative (ISFP10) with known inhibitory activity against the Aspergillus fumigatus PGM protein and exhibiting 50-fold selectivity over the human PGM enzyme homolog can also significantly reduce Pmpgm2 activity in vitro. Collectively, our data genetically and functionally validate phosphoglucomutases in both P. jirovecii and P. murina and suggest the potential of this protein as a selective therapeutic target for individuals with Pneumocystis pneumonia.


Targeting host tyrosine kinase receptor EphA2 signaling via small-molecule ALW-II-41-27 inhibits macrophage pro-inflammatory signaling responses to Pneumocystis carinii β-glucans

January 2024

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24 Reads

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3 Citations

Pneumocystis jirovecii, the fungus that causes Pneumocystis jirovecii pneumonia (PJP), is a leading cause of morbidity and mortality in immunocompromised individuals. We have previously shown that lung epithelial cells can bind Pneumocystis spp. β-glucans via the EphA2 receptor, resulting in activation and release of proinflammatory cytokines. Herein, we show that in vivo Pneumocystis spp. β-glucans activation of the inflammatory signaling cascade in macrophages can be pharmacodynamically inhibited with the EphA2 receptor small-molecule inhibitor ALW-II-41-27. In vitro, when ALW-II-41-27 is administrated via intraperitoneal to mice prior to the administration of highly proinflammatory Saccharomyces cerevisiae β-glucans in the lung, a significant reduction in TNF-alpha release was noted in the ALW-II-41-27 pre-treated group. Taken together, our data suggest that targeting host lung macrophage activation via EphA2 receptor-fungal β-glucans interactions with ALW-II-41-27 or other EphA2 receptor kinase targeting inhibitors might be an attractive and viable strategy to reduce detrimental lung inflammation associated with PJP.



Targeting Pulmonary Fibrosis by SLC1A5 Dependent Glutamine Transport Blockade

July 2023

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19 Reads

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10 Citations

American Journal of Respiratory Cell and Molecular Biology

The neutral amino acid glutamine plays a central role in TGF-β-induced myofibroblast activation and differentiation. Cells take up glutamine mainly through a transporter expressed on the cell surface known as solute carrier SLC1A5. In this current work, we demonstrated that profibrotic actions of TGF-β are mediated, at least in part, through a metabolic maladaptation of SLC1A5 and targeting SLC1A5 abrogates multiple facets of fibroblast activation. This approach could thus represent a novel therapeutic strategy to treat fibroproliferative diseases. We found that SLC1A5 was highly expressed in fibrotic lung fibroblasts and fibroblasts isolated from IPF lungs. The expression of profibrotic targets, cell migration, and anchorage independent growth by TGF-β required the activity of SLC1A5. Loss or inhibition of SLC1A5 function enhanced fibroblast susceptibility to autophagy, suppressed mTOR, HIF, Myc signaling, and impaired mitochondrial function, ATP production and glycolysis. Pharmacological inhibition of SLC1A5 by small molecule inhibitor V-9302 shifted fibroblast transcriptional profiles from profibrotic to fibrosis resolving, and attenuated fibrosis in a bleomycin treated mouse model of lung fibrosis. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in fibrosis, laying a framework for new paradigm-shifting therapies targeting cellular metabolism for this devastating disease.


Graphical representation of Pneumocystis β-glucan-mediated lung epithelial immunity. EphA2 and lactosylceramide (LacCer) functions as receptors for carbohydrates. Schematic illustration adapted from Wang et al. [69] of the most characterized lung epithelial cell carbohydrate recognition receptors for the fungal organism and brief description of the host response. Both major surface glycoprotein (gpA/Msg) and Pneumocystis β-glucan epitopes are shown with black arrows and are host receptor ligands on the Pneumocystis cell surface. Mechanism(s) for the IL-6 secretion via EphA2 receptor/Pneumocystis β-glucans engagement in airway epithelial cells is unknown.
List of lung epithelial cell lines used in immune response studies to Pneumocystis.
Lung Epithelial Cell Line Immune Responses to Pneumocystis

Pneumocystis sp. are fungal pathogens and members of the Ascomycota phylum. Immunocompetent individuals can readily eliminate the fungus, whereas immunocompromised individuals can develop Pneumocystis jirovecii pneumonia (PJP). Currently, over 500,000 cases occur worldwide, and the organism is listed on the recently released WHO fungal priority pathogens list. Overall, the number of PJP cases over the last few decades in developed countries with the use of highly effective antiretroviral therapy has decreased, but the cases of non-HIV individuals using immunosuppressive therapies have significantly increased. Even with relatively effective current anti-Pneumocystis therapies, the mortality rate remains 30–60% in non-HIV patients and 10–20% during initial episodes of PJP in HIV/AIDS patients. Although the role of alveolar macrophages is well studied and established, there is also well-established and emerging evidence regarding the role of epithelial cells in the immune response to fungi. This mini review provides a brief overview summarizing the innate immune response of the lung epithelium and various continuously cultured mammalian cell lines to Pneumocystis.


Citations (68)


... In fact, antibiotic treatment to deplete intestinal bacteria in SPF mice is an affordable and widely accessible method. Cefoperazone, a broad-spectrum third-generation cephalosporin, is often selected for its minimal systemic absorption, making it ideal for experiments on asthma where altering the lung bacterial composition is undesirable [22,23,27]. Cefoperazone sodium salt may be dissolved at a concentration of 0.5 mg/mL in deionized water and provided to mice as the only source of drinking water for 7 days. ...

Reference:

Gut Mycobiome and Asthma
The commensal fungus Wallemia mellicola enhances asthma in mice through Dectin-2
  • Citing Article
  • February 2024

Medical mycology: official publication of the International Society for Human and Animal Mycology

... Recently, we reported the presence and biochemical characterization of the Pneumocystis jirovecii and Pneumocystis murina phosphoglucomutases (PGMs) in Pneumocystis. Both PGMs complemented the Saccharomyces cerevisiae pgm2Δ strain in similar fashion and also displayed similar phosphoglucomutase activity, indicating their substantial homology and cross function (Kottom et al., 2024). In yeast, PGMs are important for carbohydrate metabolism through the interconversion of glucose 1-phosphate (Glc-1-P) and glucose 6-phosphate (Glc-6-P), a vital step in UDP pools for β-glucan cell wall formation (Yan et al., 2022). ...

Characterization of the Pneumocystis jirovecii and Pneumocystis murina phosphoglucomutases (Pgm2s): a potential target for Pneumocystis therapy

... 33 Previously mainly studied in inhibiting cancer, ALW-II-41-27 has recently been discovered potential therapeutic effects in benign diseases. 34,35 And in our primary cell, it is observed that genetic and pharmacological targeting EphA2 significantly suppressed proliferation, migration, and invasion, consistent with Matzuk. 8 Interestingly, EphA2 inhibition did not show significant inhibitory or pro-apoptotic effects in endometriosis. ...

Targeting host tyrosine kinase receptor EphA2 signaling via small-molecule ALW-II-41-27 inhibits macrophage pro-inflammatory signaling responses to Pneumocystis carinii β-glucans

... Samples were fixed in buffered formalin and embedded in paraffin. Human lung fibroblasts isolated from non-diseased lungs donated for research and from lungs explanted from patients with idiopathic pulmonary fibrosis were obtained and characterized as previously described 15 and grown in culture medium containing DMEM supplemented with 10% fetal bovine serum (FBS, Hyclone Laboratories) with assays performed at passage 3-5. Cell lines were maintained at 37 o C with 5% CO2. ...

Targeting Pulmonary Fibrosis by SLC1A5 Dependent Glutamine Transport Blockade
  • Citing Article
  • July 2023

American Journal of Respiratory Cell and Molecular Biology

... Among these microbial components, fungi have emerged as key players that influence microbial community dynamics, modulate intestinal metabolite production, and interact with immune cells to maintain immune development and homeostasis [10]. Recent studies have highlighted association between intestinal fungi and health in both humans and animals [11][12][13]. ...

Dysbiosis of the intestinal fungal microbiota increases lung resident group 2 innate lymphoid cells and is associated with enhanced asthma severity in mice and humans

Respiratory Research

... Further exploration of the Wallemia intestinal dysbiosis model revealed that Dectin-2, a Syk-coupled pattern recognition receptor, is pivotal for the gut-lung axis interactions aggravating asthma [27,35]. Dectin-2 recognizes high mannose structures and is a critical receptor for Th17 responses to fungal infections [36]. ...

Dectin-2 Recognizes Gut Dysbiosis of the Commensal Fungi Wallemia Mellicola and Is Essential for the Gut-Lung Axis Interactions Aggravating Asthma in Murine Models
  • Citing Conference Paper
  • May 2022

... Our work further underscores the role of CLR signaling through CARD9 in mediating lung inflammation during Pneumocystis pneumonia, which can promote respiratory impairment during severe disease. We have prev iously shown that a small molecule, termed BRD5529, an inhibitor of CARD9, can reduce macrophage inflammatory signaling responses to Pneumocystis b-glucans (28), but this agent has never been tested in a whole animal infection model (27). Accordingly, we assessed the effect of BRD5529 in the CD4-depleted P. murina pneumonia model (Fig. 9). ...

Preclinical and Toxicology Studies of BRD5529, a Selective Inhibitor of CARD9

Drugs in R & D

... Microbiology Spectrum of Pneumocystis infection in rats, and in animal models of lung injury (37)(38)(39). The specific host-pathogen interactions of these host vesicles and their cargo with P. carinii and P. murina are currently unknown. ...

Gene Expression in Lung Epithelial Cells Following Interaction with Pneumocystis carinii and its Specific Life Forms Yields Insights into Host Gene Responses to Infection
  • Citing Article
  • March 2022

Microbiology and Immunology

... In immunocompromised individuals, it can develop into a deadly pathogen and cause pneumonia in the correct circumstances. P. jirovecii frequently evades the host's immune system's destruction by switching to the major surface glycoprotein (MSG) antigen (49,50). In contrast to other pathogenic fungi, P. jirovecii lacks chitin and glucan in some cell cycle stages, which may inhibit the host's innate and acquired immune responses (51) (Fig. 2). ...

Current State of Carbohydrate Recognition and C-Type Lectin Receptors in Pneumocystis Innate Immunity

... A PDE4B inhibitor prevented lung function decrease in patients with idiopathic pulmonary fibrosis [9]. PDE5 inhibitors have been suggested to be antifibrotic in the heart [10] and lung [11]. ...

Vardenafil Activity in Lung Fibrosis and In Vitro Synergy with Nintedanib