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Activation of the NLRP3 inflammasome by Chlamydia infection

  • Author(s): Zhu, Ye
  • Advisor(s): Ojcius, David M
  • et al.
Abstract

The inflammasome is a multi-protein complex that serves as the first line of immune defense. NLRP3 is one of the most widely studied inflammasomes, which can be activated by a wide range of stimuli including membrane-damaging toxins, pathogen associated molecular patterns (PAMPs), and danger associated molecular patterns (DAMPs). Chlamydia is a genus of small, Gram-negative, obligate intracellular bacteria comprising four species. Among them, Chlamydia trachomatis (C.t) is the leading cause of bacterial sexual transmitted diseases (STD) worldwide, for which there are currently no effective vaccines. This is due to the difficulties in identifying and delivering relevant T cell antigens and in developing appropriate adjuvants. Vaults are large, cylindrical cytoplasmic ribonucleoprotein particles found in nearly all eukaryotic cells. Recombinant vaults that encapsulate chlamydia epitopes are highly stable structures in vitro, therefore could be employed as an ideal vaccine vehicle for epitope delivery. In the first part of this study, we tested the ability of vaults containing an immunogenic chlamydial epitope of C. trachomatis to be internalized into human monocytes and to activate the NLRP3 inflammasome. We demonstrate that chlamydia vaults co-localized with lysosomes and cathepsin B release is required for the NLRP3 inflammasome activation. Our data show that chlamydia vaults also involve in the non-canonical inflammasome and are important for inflammasome activation.

Chlamydia pneumoniae (C.pn) is an airborne chlamydial species responsible for human respiratory infection. C.pn persists within the infected tissues for periods in order to stimulate a chronic inflammatory response. The inflammation activated by C.pn is known to play an important role in the pathogenesis of atherosclerosis. C.pn has been shown to disseminate systemically from the lungs through infected peripheral blood mononuclear cells and to localize in arteries where it may infect endothelial cells, vascular smooth muscle cells, monocytes/ macrophages and promote inflammatory atherogenous process. Importantly, C.pn has recently been shown to be a new member of the human oral microbiota. It appears to be related to some oral infectious diseases including caries, periodontitis, endodonit infections, and tonsillitis. However, whether C.pn infects oral cells and induces cellular responses remains unknown. Therefore, we hypothesize that C.pn infects oral epithelial cells and activates the NLRP3 inflammasome. In the second part of this study, we provided evidence that C.pn infection activates the NLRP3 inflammasome in GECs and induces IL-1β and caspase-1 secretion. Interestingly, we also found that C.pn is frequently present in plaques from patients with periodontitis, indicating a potential correlation of periodontitis with respiratory infection or atherosclerosis.

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