cPLA2 Regulates the Expression of Type I Interferons and Intracellular Immunity to Chlamydia trachomatis

Abstract

Infection with the obligate bacterial intracellular pathogenChlamydia trachomatis leads to the sustained activation of the small GTPase RAS and many of its downstream signaling components. In particular, the mitogen-activated protein kinase ERK and the calcium-dependent phospholipase cPLA 2 are activated and are important for the onset of inflammatory responses. In this study we tested if activation of ERK and cPLA 2 occurred as a result of RAS signaling during infection and determined the relative contribution of these signaling components to chlamydial replication and survival. We provide genetic and pharmacological evidence that during infection RAS, ERK, and, to a lesser extent, cPLA 2 activation are uncoupled, suggesting that Chlamydia activates individual components of this signaling pathway in a non-canonical manner. In human cell lines, inhibition of ERK or cPLA 2 signaling did not adversely impact C. trachomatis replication. In contrast, in murine cells, inhibition of ERK and cPLA 2 played a significant protective role against C. trachomatis. We determined that cPLA 2 -deficient murine cells are permissive for C. trachomatis replication because of their impaired expression of ␤ interferon and the induction of immunity-related GTPases (IRG) important for the containment of intracellular pathogens. Furthermore, the MAPK p38 was primarily responsible for cPLA 2 activation in Chlamydia-infected cells and IRG expression. Overall, these findings define a previously unrecognized role for cPLA 2 in the induction of cell autonomous cellular immunity to Chlamydia and highlight the many non-canonical signaling pathways engaged during infection.

Chlamydia trachomatis Relies on Autonomous Phospholipid Synthesis for Membrane Biogenesis

“…The recent report identifying a C. trachomatis gene as a lyso-PC acyltransferase that functions with a host acyl-CoA-binding protein to remodel PC following C. trachomatis infection (22) is also incompatible with the analytical data. The selective degradation of polyunsaturated PE molecular species and the release of arachidonic acid into the medium are consistent with the activation of cPLA 2 observed by others (21,53,62). However, cPLA 2 activation appears to be related to the cellular immunity response to chlamydial infection rather than participating in bacterial phospholipid synthesis.…”

“…The data showed that the new PE, PG, and CL have molecular species profiles consistent with the bioinformatic model that predicts they arise from the same PA pool. 2 , and the degraded phospholipids may be subsequently modified by putative C. trachomatis acyltransferases to create new molecular species (21,53). The reduction in host PE molecular species containing polyunsaturated fatty acids in C. trachomatis-infected cultures was consistent with the degradation and/or remodeling of selected PE molecular species.…”

Type II Fatty Acid Synthesis Is Essential for the Replication of Chlamydia trachomatis

“…This work was also supported by the American Lebanese Syrian Associated Charities. The atomic coordinates and structure factors (code 4Q9N) cells found that a decrease in cPLA 2 activity has no effect on C. trachomatis growth (5). In mouse cells, cPLA 2 knockdown increases chlamydial titers, suggesting that cPLA 2 is more likely involved in intracellular immunity (5).…”

“…The atomic coordinates and structure factors (code 4Q9N) cells found that a decrease in cPLA 2 activity has no effect on C. trachomatis growth (5). In mouse cells, cPLA 2 knockdown increases chlamydial titers, suggesting that cPLA 2 is more likely involved in intracellular immunity (5). One function of FASII is to generate the 3-hydroxy fatty acids for lipopolysaccharide synthesis in Gram-negative bacteria (6).…”

Immunity-related GTPase M (IRGM) Proteins Influence the Localization of Guanylate-binding Protein 2 (GBP2) by Modulating Macroautophagy

“…Previous work from our laboratory and others has demonstrated that the IRGM (GMS) proteins play a particularly important role in innate immune resistance to intracellular bacteria and protozoa in mice (8, 14, 16 -26). Absence of Irgm1, for instance, leads to a striking susceptibility to multiple organisms, including Toxoplasma gondii (8,19), Salmonella typhimurium (25), Listeria monocytogenes (19), Chlamydia trachomatis (27,28), and Mycobacterium species (20, 21). In comparison, absence of the GKS proteins Irgd or Irga6 results in relatively weak phenotypes (8,13,19).…”