Salmonella effector AvrA promotes cellular proliferation

Abstract

Certain enteric pathogens evade elimination by secreting proteins that have potent suppressive effects on apoptosis and innate immunity. For example, the intracellular pathogen Salmonella secretes AvrA which specifically inhibits host JNK pathway signaling. We created a transgenic Drosophila harboring avrA, allowing directed expression of AvrA in fly tissues. We previously showed AvrA is a potent inhibitor of pro‐apoptotic JNK signaling in Drosophila. Here, we report that AvrA expression in a background of constitutive Eiger expression (Drosophila TNF‐alpha) resulted in increased proliferation of Drosophila epithelial tissue and importantly of Drosophila phagocytes (hemocytes) whereas AvrA activity in a non Eiger expressing background did not. Reporter gene assays in mammalian cultured cells showed AvrA mediated inhibition of JNK signaling, together with TNF‐alpha stimulation resulted in increased levels of pro‐proliferative ERK signaling. Finally, a murine Salmonella infection model showed that wild type Salmonella caused increased tissue BrdU positive splenocytes, compared to infection with an AvrA null mutant where no BrdU positive cells were detected. Together, these studies show Salmonella has evolved a protein that inhibits the pro‐apoptotic JNK pathway and also stimulates epithelial tissue and phagocyte growth under pro‐inflammatory conditions.