Mucosal-associated invariant and γδ T cell subsets respond to initial Mycobacterium tuberculosis infection

Vorkas, Charles Kyriakos; Wipperman, Matthew F.; Li, Kelin; Bean, James; Bhattarai, Shakti; Adamow, Matthew; Wong, Phillip; Aubé, Jeffrey; Juste, Marc Antoine Jean; Bucci, Vanni; Fitzgerald, Daniel W.; Glickman, Michael S.

doi:10.1172/jci.insight.121899

Cited by 62 publications

(99 citation statements)

References 91 publications

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“…Using machine learning to investigate relationships between the microbiome and peripheral gene pathways derived from the MiSigDB hallmark gene pathways database, we validated many of the relationships between peripheral gene expression and microbiome composition. We believe these results provide support to the oft stated hypothesis that there exists clear regulatory relationships between gut microbiome composition and peripheral composition, at both the immune 5 , and gene regulatory levels in humans.…”

Section: Introductionsupporting

confidence: 84%

“…Experiments in mice have demonstrated that this anti-Clostridia effect is primarily driven by rifampicin 18 . Clostridia are immunologically active components of the microbiota through their production of metabolites such as short chain fatty acids and other compounds 2,5,6,41,42 .…”

Section: Discussionmentioning

confidence: 99%

“…We used machine learning to determine the factors that predict correction or exacerbation of TB associated systemic inflammation and found that the three most important predictors are (a) the Mtb level in the sputum, (b) the abundance of Clostridia species that associate with inflammatory renormalization, and (c) the abundance of antibiotic-promoted Proteobacteria that associate with exacerbation of proinflammatory pathways. We next investigated these relationships using a validation cohort of healthy Haitian community controls and household contacts of TB patients, previously described 5 . Using machine learning to investigate relationships between the microbiome and peripheral gene pathways derived from the MiSigDB hallmark gene pathways database, we validated many of the relationships between peripheral gene expression and microbiome composition.…”

Section: Introductionmentioning

confidence: 99%

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Peripheral inflammatory response in human tuberculosis treatment is predicted by a combination of pathogen sterilization and microbiome dysbiosis

Wipperman

Bhattarai

Vorkas

et al. 2020

Preprint

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Antibiotic therapy cures infection predominantly by killing the infecting pathogen, but for infections such as tuberculosis (TB), which are accompanied by chronic inflammation, the salutary effects of antibiotic therapy may reflect a combination of pathogen killing and microbiome alteration. This question has not been examined in humans due to the difficulty in dissociating the immunologic effects of antibiotic induced pathogen clearance and microbiome alteration. We analyzed sputum TB bacterial load, microbiome composition, and peripheral blood transcriptomics from a clinical trial (NCT02684240) comparing two antimicrobial therapies for tuberculosis, only one of which was clinically effective. We confirm that standard TB therapy (HRZE) rapidly depletes Clostridia from the intestinal microbiota. The antiparasitic drug nitazoxanide (NTZ), although ineffective in reducing Mycobacterium tuberculosis (Mtb) bacterial load in the sputum, caused profound alterations to host microbiome composition overlapping with alterations generated by HRZE. We then evaluated the effect of these two treatments on the TB driven inflammatory state and found that whereas HRZE normalized proinflammatory TB-associated gene sets, NTZ exacerbated these pathways. Using Random Forest Regression, we identify both pathogen sterilization and microbiome disruption as the top predictors of changes in TB-associated inflammatory transcriptomic markers. We then validate the observed microbiome-peripheral gene expression associations in an independent human cohort of healthy subjects in which the abundance of Clostridia was positively associated with homeostatic, and negatively associated with pro-inflammatory pathways, while the abundance of Bacilli and Proteobacteria species displayed the opposite trend. Our findings indicate that antibiotic-induced reduction in pathogen burden and changes in the microbiome are independently associated with treatment-induced changes of the inflammatory response of active TB, and more broadly indicate that response to antibiotic therapy may be a combined effect of pathogen killing and microbiome driven immunomodulation. Additionally, to our knowledge, this is the first analysis to directly test the hypothesis that the microbiome composition is associated with peripheral gene expression inflammatory profile in humans.

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Section: Introductionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Peripheral inflammatory response in human tuberculosis treatment is predicted by a combination of pathogen sterilization and microbiome dysbiosis

Wipperman

Bhattarai

Vorkas

et al. 2020

Preprint

Self Cite

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“…Mycobacteria are a rich source of bacterial phosphoantigens [13], and thus, phosphoantigen-reactive Vγ9Vδ2 + T cells have been implied in protective γδ T cell responses to Mycobacterium tuberculosis infections [77,93]. Expansions of Vγ9Vδ2 + T cells in pulmonary tuberculosis (TB) have been reported [94][95][96]. Yet, in other reports, comparable to HIV infections, a loss of Vγ9Vδ2 + T cells in the blood has been observed in active TB and correlated with disease severity [92,97,98].…”

Section: Bacterial Infectionsmentioning

confidence: 99%

Human γδ TCR Repertoires in Health and Disease

Fichtner

Ravens

Prinz

2020

Cells

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The T cell receptor (TCR) repertoires of γδ T cells are very different to those of αβ T cells. While the theoretical TCR repertoire diversity of γδ T cells is estimated to exceed the diversity of αβ T cells by far, γδ T cells are still understood as more invariant T cells that only use a limited set of γδ TCRs. Most of our current knowledge of human γδ T cell receptor diversity builds on specific monoclonal antibodies that discriminate between the two major subsets, namely Vδ2+ and Vδ1+ T cells. Of those two subsets, Vδ2+ T cells seem to better fit into a role of innate T cells with semi-invariant TCR usage, as compared to an adaptive-like biology of some Vδ1+ subsets. Yet, this distinction into innate-like Vδ2+ and adaptive-like Vδ1+ γδ T cells does not quite recapitulate the full diversity of γδ T cell subsets, ligands and interaction modes. Here, we review how the recent introduction of high-throughput TCR repertoire sequencing has boosted our knowledge of γδ T cell repertoire diversity beyond Vδ2+ and Vδ1+ T cells. We discuss the current understanding of clonal composition and the dynamics of human γδ TCR repertoires in health and disease.

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“…4,5 In animal models, they drastically disrupt the microbiome within the first 7 days, allowing drug-resistant microbial species, such as Proteobacteria and Enterococcus, to subsequently proliferate, hence affecting the diversity and relative abundance of the gut microbiome. 12,13,31 Due to the importance of the microbiome in food metabolism in the intestines, their disruption affects the digestive processes, as well as the functional and biosynthetic pathways, leading to reduced biosynthesis of important metabolites and nutrients, enlarged ceca, and distorted microvilli structures. 12,32 Although fecal transplants (FTs) were able to restore much of the original diversity of the gut microbiota in animals exposed to antimicrobials, the reversal was not complete.…”

Section: Antimicrobials: the Major Enemy Of The Microbiomementioning

confidence: 99%

Mycobacterium tuberculosis, antimicrobials, immunity, and lung–gut microbiota crosstalk: current updates and emerging advances

Sekyere

Maningi

Fourie

2020

Annals of the New York Academy of Sciences

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Increasingly, gut microbiota distortions are being implicated in the pathogenesis of several infectious and noninfectious diseases. Specifically, in the absence of an eubiotic microbiota, mice are more prone to colonization and infection by Mycobacterium tuberculosis (Mtb). In this qualitative analysis, the following were observed: (1) antimicrobials cause long-term gut microbiota perturbations; (2) Mtb causes limited and transient disturbances to the lung-gut microbiota; (3) pathogens (e.g., Helicobacter hepaticus) affect microbiota integrity and reduce resistance to Mtb; (4) dysbiosis depletes bacterial species regulating proper immune functioning, reducing resistance to Mtb; (5) dysregulated immune cells fail to express important pathogen-recognition receptors (e.g., macrophageinducible C-type lectin; MINCLE) and Mtb-killing cytokines (e.g., IFN-γ, TNF-α, and IL-17), with hampered phagocytic capability; (6) autophagy is central to the immune system's clearance of Mtb, control of inflammation, and immunity-microbiome balance; (7) microbiota-produced short-chain fatty acids, which are reduced by dysbiosis, affect immune cells and increase Mtb proliferation; (8) commensal species (e.g., Lactobacillus plantarum) and microbiota metabolites (e.g., indole propionic acid) reduce tuberculosis progression; and (9) fecal transplants mostly restored eubiosis, increased immune resistance to Mtb, restricted dissemination of Mtb, and reduced tuberculosis-associated organ pathologies. Overuse of antimicrobials, as shown in mice, is a risk factor for reactivating latent or treated tuberculosis.

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Mucosal-associated invariant and γδ T cell subsets respond to initial Mycobacterium tuberculosis infection

Cited by 62 publications

References 91 publications

Peripheral inflammatory response in human tuberculosis treatment is predicted by a combination of pathogen sterilization and microbiome dysbiosis

Peripheral inflammatory response in human tuberculosis treatment is predicted by a combination of pathogen sterilization and microbiome dysbiosis

Human γδ TCR Repertoires in Health and Disease

Mycobacterium tuberculosis, antimicrobials, immunity, and lung–gut microbiota crosstalk: current updates and emerging advances

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