With 8.9 million new cases and 1.3 million deaths per year, tuberculosis (TB) is a leading global epidemic that has not been effectively controlled. The causative agent, Mycobacterium tuberculosis (M.tb), proliferates within host macrophages where it modifies both its intracellular and local tissue environment to facilitate survival within caseous granulomas. We have demonstrated that M.tb produces a bacterial-specific molecule, cyclic-di- AMP (c-di-AMP), which subverts host cell immune responses. We have generated recombinant M.tb strains that overexpress c-di-AMP or lack c-di-AMP production, as well as a complement strain as a control. Using these strains we found that c-di-AMP induces a Type I response via the cytosolic surveillance pathway (CSP) and increases autophagy. Consequently, overexpression of c-di-AMP leads to attenuation while the absence of this molecule results in hyper-virulence in the mouse model of M.tb. Furthermore, these recombinant strains have demonstrated an important role for c-di-AMP within M.tb in regulating biofilm formation and antibiotic susceptibility. Based on our findings, we hypothesize that c-di-AMP regulates M.tb physiology and modulates host immune response to infection. This application will determine how c-di-AMP balances the interplay between the Type-I IFN response, IL-1 production and autophagy induction in the host (Aim 1). It will also explore the role of c-di-AMP in M.tb physiology by identifying its receptor in M.tb and assessing its contribution to a stress response (Aim 2). Finally, it will determine the adjuvant potential of c-di-AMP in inducing protective immunity against tuberculosis (Aim 3).
Cyclic-di-AMP, a recently identified bacterial product, modifies host immune response; we have observed that excessive production of this molecule by tuberculosis-inducing bacteria results in attenuation of tuberculosis, while absence of its production results in hyper-virulence. Our proposed research will further identify mechanisms by which c-di-AMP subverts immune response in the host, and will also study its potential to provide immunity against tuberculosis. Our understanding of the role of this molecule in the host will allow us to develop therapeutic approaches that are beneficial to the host.
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