Salmonella evades host innate immunity via AvrA mediated inhibition of cytokine production and pro‐apoptotic pathways

Abstract

The enteric pathogen Salmonella typhimurium suppresses host innate immune responses via secretion of preformed effector proteins into host cells during invasion. One of these proteins, AvrA, has potent immunosuppressive and anti‐apoptotic effects in mammalian cultured cells and in a Drosophila animal model via inhibition of the JNK pathway. To study the role of AvrA in a murine model of natural infection, wild type Salmonella harboring AvrA or an isogenic AvrA null mutant Salmonella were orally administered to mice pretreated with streptomycin and infectious phenotypes compared. Infection with the AvrA null Salmonella caused increased levels of apoptosis in the cecal epithelium and in lymphoid resident monocytic cells at 6h post infection. Additionally, the AvrA null Salmonella induced increased serum cytokine levels, including KC, IL‐1beta and TNFalpha. Furthermore, AvrA null Salmonella caused increased hepatosplenomegaly by 7 days post infection. This coincided with increased bacterial load in the liver, spleen and mesenteric lymph node, and more severe weight loss. We conclude that Salmonella evades host innate immunity and gains systemic access/dissemination via AvrA mediated inhibition of cytokine production and apoptosis. Research funding provided by NIH AI 64462.