| When bacterial pathogens infect their hosts, they elicit responses intended on containing and eliminating these invaders. These events allow the host to produce antimicrobial agents and help recruit components of the immune system to help fight the infection. If an invading pathogen is well adapted to the environment, it is able capable to subvert this anti-microbial response and may even harness it to its benefit. The Gram-negative bacteria Chlamydia trachomatis is one example of an intracellular pathogen capable of manipulating host cell signaling for its own benefit. Infection with this obligate bacterial intracellular pathogen 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 cPLA2 are activated and are important for the onset of inflammatory responses during chlamydial infection. In this study we tested whether activation during infection of ERK and cPLA2 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 activation of Ras, ERK and, to a lesser extent, cPLA2 are activated by Chlamydia 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 cPLA2, and to a lesser extent ERK, played a significant protective role against C. trachomatis. Finally, we determined that cPLA2-deficient murine cells are permissive for C. trachomatis replication due to impaired expression of beta-interferon and the induction of Immunity-Related GTPases (IRGs) important for the containment of intracellular pathogens. Overall, these findings define a previously unrecognized role for cPLA2 in the induction of cell autonomous immunity to Chlamydia. |
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