Humans are infected by Mycobacterium tuberculosis (MTB), the cause of tuberculosis (TB), primarily by inhaling aerosolized bacteria. Most individuals require adaptive T cell immunity to control MTB. The hallmark of this host-pathogen interaction is that, despite T cell immunity's control of bacillary growth, T cells do not eradicat MTB. Thus T cells and infected antigen presenting cells (APC) are not only central for control of MTB but also targets of its immune evasion strategies. Our studies have demonstrated that MTB interferes with T cell recognition of infected cells. We have used a strategy starting with MTB fractions followed by purification of MTB molecules that directly affect T cell function or antigen processing. Once an MTB molecule is identified, the molecular mechanism is determined. To date, we have identified 4 MTB mechanisms that affect T cell function: 2 inhibit and 2 activate human T cells. PIM and Rv2468c interact with VLA-5 on T cells to induce adhesion to fibronectin;lipoproteins can co-stimulate T cells through TLR-2. In contrast MTB lipoproteins through TLR-2 inhibit MHC-II antigen processing by macrophages;and (our most recent discovery) ManLAM inhibits proximal T cell receptor signaling (TCR) in a TLR-2 independent manner. Inhibition of TCR signaling by ManLAM, the most recent mechanism that we have discovered, forms the focus of this competing renewal application for the following reasons. First, ManLAM is one of the most abundant glycolipids in the MTB cell wall. Second, ManLAM travels outside the phagosome to interact with host cells. Third, ManLAM is readily found in exosomes and microvesicles produced by MTB infected cells, providing a mechanism for direct delivery to T cells. Fourth, ManLAM inserts into host cell membranes. Fifth, ManLAM represents the most direct mechanism so far for interdicting T cell response during both latent MTB infection and active TB. Thus ManLAM's interference with TCR signaling represents a second major mechanism for interfering with T cell activation and that sensitivity to this inhibitoy effect may affect one's ability to control or eliminate latent bacilli.
The aims are:
Aim 1. To determine the molecular mechanism of inhibition of TCR signaling by ManLAM in terms of how ManLAM is delivered to T cells, how and where it inserts in the T cell membrane and how it interferes with TCR function and T cell-APC conjugate formation, and ManLAM's structural requirements for inhibition.
Aim 2. To determine the functional consequences of ManLAM inhibition of CD4+ T cell activation in terms of recovery of inhibition, induction of apoptosis or anergy, differential effects on non-CD4+ T cells and synergy with inhibition of MHC-II antigen processing.
Aim 3. To determine the ability of ManLAM to inhibit T cell responses to MTB in vivo using the murine MTB infection model and determining if there is variable sensitivity to ManLAM among humans.

Public Health Relevance

Understanding how M. tuberculosis, the cause of human tuberculosis (TB), evades the immune system controlled by T cells so that it persists in a dormant state to cause disease many years later, is essential not only for host-pathogenesis studies but also for development and testing of new T cell vaccines for TB. Variable sensitivity to M. tuberculosis'T cell immune evasion strategies may be a factor in susceptibility to progression from M. tuberculosis infection to disease and in a person's ability to effectively clea M. tuberculosis bacilli with drug therapy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Lacourciere, Karen A
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Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
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Karim, Ahmad Faisal; Reba, Scott M; Li, Qing et al. (2017) Toll like Receptor 2 engagement on CD4+ T cells promotes TH9 differentiation and function. Eur J Immunol 47:1513-1524
Athman, Jaffre J; Sande, Obondo J; Groft, Sarah G et al. (2017) Mycobacterium tuberculosis Membrane Vesicles Inhibit T Cell Activation. J Immunol 198:2028-2037
Karim, Ahmad F; Sande, Obondo J; Tomechko, Sara E et al. (2017) Proteomics and Network Analyses Reveal Inhibition of Akt-mTOR Signaling in CD4+ T Cells by Mycobacterium tuberculosis Mannose-Capped Lipoarabinomannan. Proteomics 17:
Li, Qing; Karim, Ahmad F; Ding, Xuedong et al. (2016) Novel high throughput pooled shRNA screening identifies NQO1 as a potential drug target for host directed therapy for tuberculosis. Sci Rep 6:27566
Sande, Obondo J; Karim, Ahmad F; Li, Qing et al. (2016) Mannose-Capped Lipoarabinomannan from Mycobacterium tuberculosis Induces CD4+ T Cell Anergy via GRAIL. J Immunol 196:691-702
Athman, Jaffre J; Wang, Ying; McDonald, David J et al. (2015) Bacterial Membrane Vesicles Mediate the Release of Mycobacterium tuberculosis Lipoglycans and Lipoproteins from Infected Macrophages. J Immunol 195:1044-53
Richardson, Edward T; Shukla, Supriya; Sweet, David R et al. (2015) Toll-like receptor 2-dependent extracellular signal-regulated kinase signaling in Mycobacterium tuberculosis-infected macrophages drives anti-inflammatory responses and inhibits Th1 polarization of responding T cells. Infect Immun 83:2242-54
Richardson, Edward T; Shukla, Supriya; Nagy, Nancy et al. (2015) ERK Signaling Is Essential for Macrophage Development. PLoS One 10:e0140064
Shukla, Supriya; Richardson, Edward T; Athman, Jaffre J et al. (2014) Mycobacterium tuberculosis lipoprotein LprG binds lipoarabinomannan and determines its cell envelope localization to control phagolysosomal fusion. PLoS Pathog 10:e1004471
Liu, Zhuoming; Reba, Scott; Chen, Wei-Dong et al. (2014) Regulation of mammalian siderophore 2,5-DHBA in the innate immune response to infection. J Exp Med 211:1197-213

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