Chlamydia induced caspase-1 activation is inflammasome dependent: role and sources of reactive oxygen species in chlamydial growth
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Chlamydia induced caspase-1 activation is inflammasome dependent: role and sources of reactive oxygen species in chlamydial growth

  • Author(s): Sater, Ali Abbas Abdul
  • Advisor(s): Ojcius, David M.
  • et al.
Abstract

Inflammasomes have been extensively characterized in monocytes and macrophages, but not in epithelial cells, which are the preferred host cells for many pathogens. Here we show that cervical epithelial cells express a functional inflammasome. Infection of the cells by Chlamydia trachomatis leads to activation of caspase-1, through a process requiring the NOD-like receptor family member NLRP3 and the inflammasome adaptor protein ASC. Secretion of newly synthesized virulence proteins from the chlamydial vacuole through a type III secretion apparatus results in efflux of K+ through glibenclamide-sensitive K+ channels, which in turn stimulates production of reactive oxygen species. Elevated levels of reactive oxygen species (ROS) are responsible for NLRP3-dependent caspase-1 activation in the infected cells. In monocytes and macrophages, caspase-1 is involved in processing and secretion of proinflammatory cytokines such as interleukin-1β. We demonstrate that C. trachomatis or C. muridarum infection of a monocytic cell line lead to caspase-1 dependent interleukin-1β (IL-1β) secretion in a NLRP3 inflammasome dependent manner that requires Syk signaling. However, in epithelial cells, which are not known to secrete large quantities of IL-1β, caspase-1 has been shown previously to enhance lipid metabolism. Here we show that, in cervical epithelial cells, caspase-1 activation is required for optimal growth of the intracellular chlamydiae. Given the importance of ROS-induced caspase-1 activation in growth of chlamydial inclusion, we further investigate the sources of ROS production in epithelial cells following infection with C. trachomatis. In this study, we provide evidence that NLRX1-dependent mitochondrial generation of ROS is one of the two sources of ROS production induced by chlamydial infection; the other source being NADPH oxidase.

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