Recognition of Mycobacterium tuberculosis by the host inflammasome Public Deposited

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  • March 22, 2019
  • McElvania TeKippe, Erin
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
  • The NLR gene family mediates host immunity to various acute pathogenic stimuli but its role in chronic infection is not known. This thesis addressed the role of NLRP3 (NALP3), its adaptor protein ASC, and caspase-1 during infection with Mycobacterium tuberculosis (Mtb). Mtb infection of macrophages in culture induced IL-1[beta] secretion, and this requires the inflammasome components ASC (also PYCARD, TMS1), caspase-1, and NLRP3. However in vivo Mtb aerosol infection of Nlrp3-/-, Casp-1-/- , and WT mice showed no differences in pulmonary IL-1[beta] production, bacterial burden, or long-term survival. In contrast, a significant role was observed for ASC in host protection during chronic Mtb infection, as shown by an abrupt decrease in survival of ASC-/- mice. Decreased survival of Mtb-infected ASC-/- animals was associated with defective granuloma formation and reduced CD11c+ CD11bmid/low cells. ASC is known to bind the noninflammasome forming protein Nlrp12in an artificial expression system. Following Mtb infection, Nlrp12-/- mice had similar survival, bacterial burden, and cytokines to the wild-type controls, indicating that Nlrp12 does not protect the host during Mtb infection. These data demonstrate that ASC exerts a novel inflammasome-independent role during chronic Mtb infection.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the department of Microbiology and Immunology, School of Medicine
  • Ting, Jenny P.-Y.

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