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Mycobacterium tuberculosis tRNA triggers TLR8 to induce a pathway for Th1 cell instruction

  • Author(s): Keegan, Caroline
  • Advisor(s): Modlin, Robert
  • et al.
Abstract

Mycobacterium tuberculosis, the etiologic agent of tuberculosis, has infected one third of the world’s population and is one of the leading global infectious disease threats. Treatment is challenging, lasting upwards of six months even for drug sensitive infections, and the proliferation of multi and extensively drug resistant forms of tuberculosis underscore the urgent need for knowledge of the mechanisms driving pathogenesis of this disease. The ability of the innate immune system to combat infection involves activation of pattern recognition receptors (PRRs) that detect evolutionarily conserved pathogen-associated molecular patterns, including nucleic acids and lipoproteins. Activation of PRRs, including Toll-like receptors (TLRs), induces secretion of inflammatory and immunomodulatory cytokines that instruct adaptive immune pathways for T cell differentiation. For intracellular pathogens like M. tuberculosis, a Th1 response is required, whereas a Th2 response is beneficial for the control of extracellular parasites, but is associated with active tuberculosis disease. This dissertation seeks to understand modulators of the initial immune response to M.�tuberculosis through characterization of innate immune pathways induced by distinct bacterial ligands. The first study explores a mechanism by which Th1 or Th2 cytokines alter the vitamin D-dependent antimicrobial pathway in response to M.�tuberculosis 19kD lipoprotein, and illustrates the importance of the Th1 cytokine IFN-g in guiding an antimicrobial response. Next, is a comparison of the immune response induced by the M.�tuberculosis-derived ligands: 19kD lipoprotein and purified tRNA. M. tuberculosis tRNA was found to induce a gene network inducing secretion of key Th1 cytokines including IL-12p70 and IFN-g, which are necessary for host defense against TB.

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