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Flow chart of TB disease progression and major events leading to protection. Major steps are outlined for the progression of and infected or uninfected hosts from the point of exposure to development of active disease or clinical latency (protection). The relative percentage of individuals to progress between steps is shown beside the appropriate progression line.
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Mycobacterium tuberculosis (M.tb), the causative bacterium of pulmonary tuberculosis (TB), is a serious global health concern. Central to M.tb effective immune avoidance is its ability to modulate the early innate inflammatory response and prevent the establishment of adaptive T-cell immunity for nearly three weeks. When compared with other intrace...
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Citations
... On the other hand, they activate the adaptive immune response by migrating to lymph nodes and priming naive T lymphocytes [64]. Mtb uses various mechanisms to disrupt these processes and delay the formation of the adaptive immune response [65]. When effector T cells eventually arrive at the site of infection, they activate macrophages via cytokines, primarily interferon gamma (INF-γ), which leads to the enhanced bactericidal action of macrophages. ...
Mycobacterium tuberculosis (Mtb) is one of the most successful bacterial pathogens in human history. Even in the antibiotic era, Mtb is widespread and causes millions of new cases of tuberculosis each year. The ability to disrupt the host’s innate and adaptive immunity, as well as natural persistence, complicates disease control. Tuberculosis traditional therapy involves the long-term use of several antibiotics. Treatment failures are often associated with the development of resistance to one or more drugs. The development of medicines that act on new targets will expand treatment options for tuberculosis caused by multidrug-resistant or extensively drug-resistant Mtb. Therefore, the development of drugs that target virulence factors is an attractive strategy. Such medicines do not have a direct bacteriostatic or bactericidal effect, but can disarm the pathogen so that the host immune system becomes able to eliminate it. Although cell wall-associated targets are being actively studied for anti-TB drug development, other virulence factors important for adaptation and host interaction are also worth comprehensive analysis. In this review, specific Mtb virulence factors (such as secreted phosphatases, regulatory systems, and the ESX-1 secretion system) are identified as promising targets for novel anti-virulence drug development. Additionally, models for the search of virulence inhibitors are discussed, such as virtual screening in silico, in vitro enzyme inhibition assay, the use of recombinant Mtb strains with reporter constructs, phenotypic analysis using in vitro cell infection models and specific environments.
... Many factors influence the arrival of T cells at the site of infection, including constraints on effective antigen presentation processes and the highly suppressive expansion of regulatory T-cell (Treg) populations, which limits the initiation and proliferation of effector T cells [7][8][9]. In the process of tuberculosis infection, chemokines secreted by inflammatory macrophages are also important factors affecting the infiltration of T cells into the site of infection [10]. ...
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a critical global health issue that is complicated by the ability of the pathogen to delay the host’s T-cell immune response. This delay in T-cell recruitment to the site of infection is a pivotal survival strategy for Mtb, allowing it to establish a persistent chronic infection. To investigate the underlying mechanisms, this study focused on Mtb’s exploitation of host tryptophan metabolism. Mtb upregulates indoleamine 2,3-dioxygenase 1 (IDO1) in inflammatory macrophages, thereby increasing kynurenine (Kyn) production. Kyn then activates the aryl hydrocarbon receptor (AhR), leading to the upregulation of suppressor of cytokine signaling 3 and subsequent inhibition of the JAK-STAT1 signaling pathway. This results in reduced secretion of the chemokines CXCL9 and CXCL10, which are crucial for T-cell recruitment to the lungs. Supported by in vivo mouse models, our findings reveal that disrupting this pathway through AhR knockout significantly enhances T-cell infiltration and activity, thereby undermining Mtb-induced immunosuppression. In contrast, additional Kyn injection obviously inhibited T-cell infiltration and activity. These results highlight potential therapeutic targets of AhR and IDO1, offering new avenues for enhancing the host immune response against tuberculosis and guiding future vaccine development efforts.
... reduction in total neutrophil recruitment, underlining the importance of the caspase-1-dependent pathway for the inflammatory loop involving neutrophils in the lung. In our study, restricted to one time point corresponding to early orchestration of the adaptive T-cell response in the lungs (16,39), we observed that caspase-dependent IL-1β production mainly affected the recruitment of inflammatory neutrophils and CD4 T cells. The link between IFN-γ-producing CD4 T cells and excessive neutrophilia during clinical manifestations of TB has been clearly established (40), and we observed high recruitment of IL-1β-producing inflammatory neutrophils in IFN-γR −/− mice that correlated with elevated levels of CD4 T cells and IFN-γ and highly lesioned lungs. ...
Neutrophils can be beneficial or deleterious during tuberculosis (TB). Based on the expression of MHC-II and programmed death ligand 1 (PD-L1), we distinguished two functionally and transcriptionally distinct neutrophil subsets in the lungs of mice infected with mycobacteria. Inflammatory [MHC-II ⁻ , PD-L1 lo ] neutrophils produced inflammasome-dependent IL-1β in the lungs in response to virulent mycobacteria and “accelerated” deleterious inflammation, which was highly exacerbated in IFN-γR −/− mice. Regulatory [MHC-II ⁺ , PD-L1 hi ] neutrophils “brake” inflammation by suppressing T-cell proliferation and IFN-γ production. Such beneficial regulation, which depends on PD-L1, is controlled by IFN-γR signaling in neutrophils. The hypervirulent HN878 strain from the Beijing genotype curbed PD-L1 expression by regulatory neutrophils, abolishing the braking function and driving deleterious hyperinflammation in the lungs. These findings add a layer of complexity to the roles played by neutrophils in TB and may explain the reactivation of this disease observed in cancer patients treated with anti-PD-L1.
... 47 The diabetic mouse model of TB infection also demonstrates impaired trafficking of immune cells, resulting in delayed T cell responses, resulting in increased susceptibility to infection with MTB. 48,49 Our data, although in a small subgroup of cases with controlled hyperglycaemia, suggest that IFN-γ activation may be impacted in individuals with uncontrolled DM possibly leading to reduced immunity against MTB. This hypothesis is further supported by the observation that differences in PPD-induced SOCS1 mRNA expression between the study groups were only observed in DM with controlled glycaemia as compared with EC. ...
Tuberculosis (TB) outcomes are worsened by type II diabetes mellitus (DM). Protective immunity against Mycobacterium tuberculosis (MTB) is driven by cytokines. Latent TB (LTBi) is common but its effect on the diabetic host is not well understood. We investigated mycobacterial antigen stimulated responses in peripheral blood mononuclear cell (PBMC) isolated from healthy endemic controls (EC), those with LTBi, DM groups with and without LTBi, as compared with TB patients. Cytokines were measured using a Luminex based assay. Gene expression was determined by RT-PCR. In DM-LTBi cases, PPD-stimulated pro-inflammatory cytokines; IFN-γ, IL-6, IL-2, TNF-α and GM-CSF and anti-inflammatory cytokines, IL-5 and IL-13 were raised as compared with EC. DM-LTBi PPD-stimulated IFN-γ, IL-6 and TNF-α mRNA titers were found raised in DM-LTBi whilst, suppressor of cytokine signaling (SOCS)-3 expression was lowered. Within DM cases, stratification based on HbA1c levels revealed raised IFN-γ but lowered IL-6 gene expression in those with controlled levels as compared with uncontrolled glycemic levels. Further, SOCS1 expression levels were found higher in DM cases with controlled glycemia when compared with EC. Overall, we show that diabetics with LTBi manifest raised levels of inflammatory and anti-inflammatory cytokines concomitant with reduced SOCS3 mRNA expression. Reduced glycemic control results in further inflammatory dysregulation impacting conversing impacting IFN-γ and IL-6 activation. These results suggest that dysregulated immune activation in diabetes is exacerbated by LTBi, lack of glycemic control may further compromise immunity against MTB infection.
... As there are not many experimental or clinical studies focused on humans, many parameters are derived from animal models or have been estimated. Where parameters have been estimated, large ranges have been applied as well as a uniform distribution (Shaler et al., 2012). The uncertainty created by these estimated parameters is explored in Section 5. ...
Progress in shortening the duration of tuberculosis (TB) treatment is hampered by the lack of a predictive model that accurately reflects the diverse environment within the lung. This is important as TB has been shown to produce distinct localisations to different areas of the lung during different disease stages, with the environmental heterogeneity within the lung of factors such as air ventilation, blood perfusion and oxygen tension believed to contribute to the apical localisation witnessed during the post-primary form of the disease.
Building upon our previous model of environmental lung heterogeneity, we present a networked metapopulation model that simulates TB across the whole lung, incorporating these notions of environmental heterogeneity across the whole TB life-cycle to show how different stages of the disease are influenced by different environmental and immunological factors. The alveolar tissue in the lung is divided into distinct patches, with each patch representing a portion of the total tissue and containing environmental attributes that reflect the internal conditions at that location. We include populations of bacteria and immune cells in various states, and events are included which determine how the members of the model interact with each other and the environment. By allowing some of these events to be dependent on environmental attributes, we create a set of heterogeneous dynamics, whereby the location of the tissue within the lung determines the disease pathological events that occur there.
Our results show that the environmental heterogeneity within the lung is a plausible driving force behind the apical localisation during post-primary disease. After initial infection, bacterial levels will grow in the initial infection location at the base of the lung until an adaptive immune response is initiated. During this period, bacteria are able to disseminate and create new lesions throughout the lung. During the latent stage, the lesions that are situated towards the apex are the largest in size, and once a post-primary immune-suppressing event occurs, it is the uppermost lesions that reach the highest levels of bacterial proliferation. Our sensitivity analysis also shows that it is the differential in blood perfusion, causing reduced immune activity towards the apex, which has the biggest influence of disease outputs.
... However, the progress made in investigating T cell immunity suggests the sequestration of peripheral Th1 cells within the vasculature in early stages of pulmonary M.tb infection to be a mechanism. 49,67 Unfortunately, even parenteral BCG-activated Th1 cells are unable to effectively overcome such barrier due to M.tb-imposed local innate immune tolerance. 68 In the recent years, however, the growing body of evidence suggests that besides its effects on Ag-specific T cells, parenteral BCG vaccination has a profound nonspecific effect on innate immune cells, particularly the circulating monocytes. ...
In the past few years, our understanding of immunological memory has evolved remarkably due to a growing body of new knowledge in innate immune memory and immunity. Immunological memory now encompasses both innate and adaptive immune memory. The hypo‐reactive and hyper‐reactive types of innate immune memory lead to a suppressed and enhanced innate immune protective outcome, respectively. The latter is also named trained innate immunity (TII). The emerging information on innate immune memory has not only shed new light on the mechanisms of host defense but is also revolutionizing our long‐held view of vaccination and vaccine strategies. Our current review will examine recent progress and knowledge gaps in innate immune memory with a focus on tissue‐resident Mϕs, particularly lung Mϕs, and their relationship to local antimicrobial innate immunity. We will also discuss the impact of innate immune memory and TII on our understanding of vaccine concept and strategies and the significance of respiratory mucosal route of vaccination against respiratory pathogens. Review on innate immune memory; focuses particularly on tissue‐resident Mϕs, anti‐microbial innate immunity, and vaccine strategies.
... A portion of these droplets contain Mycobacterium tuberculosis. Therefore, in the event that someone close by inhales these droplets, they become exposed and may become infected with a probability of 30% [43]. Refer to Figure 2.4 for the flow chart containing the probabilities of contracting TB once exposed [43]. ...
... Therefore, in the event that someone close by inhales these droplets, they become exposed and may become infected with a probability of 30% [43]. Refer to Figure 2.4 for the flow chart containing the probabilities of contracting TB once exposed [43]. ...
... TBType is set to indicate which strain of TB the agent has been exposed to. The transition from Exposed to LatentTB is according to a probability of 30% as per research indications [43]. In the event that this is true, the variable SetToLatent is set to 'true' and this change forces the agent to change states as a result of the condition-trigger. ...
In South Africa, it is approximated that 13.9% of residents live in informal settlements, with this �figure increasing to 20% in metropolitan areas. These settlements are characterised by derelict housing conditions, high population density and lack of access to amenities such as refuse removal, sanitation, water and electricity. Due to the high population density of informal settlements, the spread of communicable diseases is highly effective in this environment. Furthermore, South Africa has been on the World Health Organisation's list of 30 top tuberculosis burdened countries in the world for the last two decades, which may be explained due to high rates of human immunodeficiency virus cases. The rate of individuals diseased with tuberculosis in informal settlements, however, are reported to be double that of the country. Although there is much uncertainty surrounding these factors as underreporting of tuberculosis is a problem in South Africa. In order to succeed in reducing the number of tuberculosis cases, policy decision makers have a growing need to understand the risk factors surrounding tuberculosis and data
which may inform their decision in a quantifiable manner.
In this study, agent-based simulation is employed in order to facilitate the understanding of the spread of tuberculosis in these environments. The simulation model developed aims to achieve this through modelling the personal characteristics, daily movements and interactions between informal settlement residents. This model is able, within a certain range of accuracy, to indicate the spread of tuberculosis given certain input parameters, such as population size, probability of treatment termination and percentage initially infected, amongst others. This may assist policy makers in making informed decisions based on quantitative targets. Verification and validation techniques are applied in order to build confidence in the reliability of the model to be used as such a tool. The model is subjected to face validation, as well as other techniques such as sensitivity analysis and parameter variation. Interesting model insight gained included the high impact that the spread radius and the probability of terminating treatment has on the spread. It is evident that population density had a great impact on the spread rate of the disease. This is supportive of the fact that 90% of residents in informal settlements have latent tuberculosis. Given that only 68% of people with the disease seek treatment, by increasing this likelihood through incentives, it is possible to drastically decrease the rate of death and unsuccessful treatment.
... Of the 30% that do become infected, over 90% of individuals are able to contain the bacilli in a granuloma; leading to latent infection. 10 Although HIV and other forms of immunosuppression increase the likelihood of developing disease, increase the severity of symptoms, and decrease the time to progression, 11,12 the reasons why most individuals exposed to M.tb do not develop TB are not known. ...
Exciting clinical results from 2 clinical TB vaccine trials were published in 2018. These, plus promising preclinical candidates form a healthy pipeline of potential vaccines against the leading cause of death from a single infectious agent. The only licensed vaccine, the BCG, continues to be an important tool in protecting against severe forms of TB in children, but has not stopped the diseases causing 1.3 million deaths per year. This review provides an overview of the current TB vaccine pipeline, highlighting recent findings, describes work relating to epidemiologic impact of vaccines, and discusses the future of TB vaccine development.
... In BCG-vaccinated cattle, boosting via endobronchial administration with AdAg85A induces local and systemic responses that are similar in magnitude to intradermal boosting 11,12 . Vaccine-induced protection that is observed after aerosol and endobronchial immunization is believed to be associated with the preferential recruitment of antigen-specific CD4 T cells to the lung airways 5,13-18 , which allows for an immediate response upon pathogen exposure, preventing bacilli from establishing infection [19][20][21] . While it is clear that IFNγ-secreting CD4 T cells are an essential component for protection against TB, IFNγ secretion is a poor correlate of protection 22,23 . ...
The Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine is administered parenterally to infants and young children to prevent tuberculosis (TB) infection. However, the protection induced by BCG is highly variable and the vaccine does not prevent pulmonary TB, the most common form of the illness. Until improved TB vaccines are available, it is crucial to use BCG in a manner which ensures optimal vaccine performance. Immunization directly to the respiratory mucosa has been shown to promote greater protection from TB in animal models. γδ T cells play a major role in host defense at mucosal sites and are known to respond robustly to mycobacterial infection. Their positioning in the respiratory mucosa ensures their engagement in the response to aerosolized TB vaccination. However, our understanding of the effect of respiratory BCG vaccination on γδ T cell responses in the lung is unknown. In this study, we used a calf model to investigate the immunogenicity of aerosol BCG vaccination, and the phenotypic profile of peripheral and mucosal γδ T cells responding to vaccination. We observed robust local and systemic M. bovis-specific IFN-γ and IL-17 production by both γδ and CD4 T cells. Importantly, BCG vaccination induced effector and memory cell differentiation of γδ T cells in both the lower airways and peripheral blood, with accumulation of a large proportion of effector memory γδ T cells in both compartments. Our results demonstrate the potential of the neonatal calf model to evaluate TB vaccine candidates that are to be administered via the respiratory tract, and suggest that aerosol immunization is a promising strategy for engaging γδ T cells in vaccine-induced immunity against TB.
... Its complex cell-wall and secretome interferes with innate immune signaling pathways of the host, which culminates in a delayed onset of adaptive response at the primary site of infection. This delayed immune activation favors an exponential growth of M.tb and the successful establishment of infections (1). ...
... This analysis was undertaken by challenging the mice with M.tb at two time points i.e., 4 weeks (Group 1) and 8 weeks (Group 2) after MIP vaccination. In general, the T-cell response should peak at 2 weeks after infection but M.tb mediated host modulation delays the response by 1 additional week (1). However, in comparison to the only infected "control, " our results demonstrated the presence of significantly higher numbers of CD4 + (p = 0.032) and CD8 + (p = 0.021) T EM cells in airway lumen at 2 weeks after M.tb infection in Group 1. ...
The lungs are the most vulnerable site for air-borne infections. Immunologic compartmentalization of the lungs into airway lumen and interstitium has paved the way to determine the immune status of the site of pathogen entry, which is crucial for the outcome of any air-borne infections. Vaccination via the nasal route with Mycobacterium indicus pranii (MIP), a prospective candidate vaccine against tuberculosis (TB), has been reported to confer superior protection as compared to the subcutaneous (s.c.) route in small-animal models of TB. However, the immune mechanism remains only partly understood. Here, we showed that intranasal (i.n.) immunization of mice with MIP resulted in a significant recruitment of CD4⁺ and CD8⁺ T-cells expressing activation markers in the lung airway lumen. A strong memory T-cell response was observed in the lung airway lumen after i.n. MIP vaccination, compared with s.c. vaccination. The recruitment of these T-cells was regulated primarily by CXCR3–CXCL11 axis in “MIP i.n.” group. MIP-primed T-cells in the lung airway lumen effectively transferred protective immunity into naïve mice against Mycobacterium tuberculosis (M.tb) infection and helped reducing the pulmonary bacterial burden. These signatures of protective immune response were virtually absent or very low in unimmunized and subcutaneously immunized mice, respectively, before and after M.tb challenge. Our study provides mechanistic insights for MIP-elicited protective response against M.tb infection.