Salmonella effector protein AvrA influences bacterial dissemination and persistence within the host

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Certain pathogens stably establish themselves within host cells because they have evolved mechanisms to evade elimination. For example, the intracellular enteric pathogen Salmonella secretes the AvrA acyltransferase which has suppressive effects on innate immunity and apoptosis. To determine the mechanism by which AvrA mediates these effects, we created transgenic Drosophila harboring avrA. We show that AvrA has potent and specific inhibitory activity against the JNK pathway in Drosophila and in mammalian epithelial cells. Intriguingly, we also found that AvrA expression in a background of proinflammatory stimulation resulted in increased cellular proliferation. Mechanistic assays in cultured cells showed AvrA mediated inhibition of the JNK pathway and concurrent TNF stimulation resulted in elevated ERK pathway signaling. Polarized T84 cultured cells, or primary murine bone marrow cells infected with an adenovirus expressing AvrA and stimulated with TNF also exhibited elevated proliferation compared to unstimulated or uninfected cells. Finally, elevated BrdU positive splenocytes were observed in mice infected with wild type Salmonella compared to mice infected with mutant Salmonella avrA‐. Together, these data show Salmonella has evolved a protein that influences MAPK pathways with the effect of facilitating Salmonella persistence and growth by forcing cellular proliferation.