Salmonella Typhimurium promotes cholesterol accumulation and bacterial survival in host macrophages through the cholesterol acyltransferase activity of the SPI-2 effector protein SseJ
Greene, Adam, Microbiology - School of Medicine, University of Virginia
Casanova, James, MD-CELL Cell Biology, University of Virginia
Upon infection of host cells, Salmonella enterica serovar Typhimurium resides in a modified endosomal compartment referred to as the Salmonella-containing vacuole (SCV). Following invasion of host cells, Salmonella uses multiple effector proteins translocated through two type III secretion systems (T3SS-1 and T3SS-2) to alter the host environment and manipulate intracellular signaling. While many host proteins targeted by effector proteins have been characterized, the role of host lipids in Salmonella pathogenesis remains poorly understood. Previous studies have shown that S. Typhimurium infection in macrophages leads to accumulation of intracellular cholesterol, much of which concentrates in and around SCVs; however, the underlying mechanisms for cholesterol accumulation and the role of cholesterol in S. Typhimurium virulence remains unknown. Here, we show that S. Typhimurium utilizes the T3SS-2 effector SseJ to downregulate expression of the host cholesterol transporter ABCA1 and increase cellular free cholesterol during infection of macrophages. We identify a novel role for SseJ in the activation of the host kinases FAK and Akt and the enrichment of host intracellular cholesterol concentrations through the suppression of Abca1. Pharmacological induction of Abca1 prevents cholesterol accumulation and attenuates S. Typhimurium survival, while the depletion of Abca1 restores Salmonella survival in FAK-deficient macrophages, suggesting that the inhibition of cholesterol efflux and increased intracellular cholesterol plays an important role in Salmonella pathogenesis. Collectively, these findings highlight the importance of manipulating host lipid homeostasis and suggests a critical role for cholesterol in promoting Salmonella survival in macrophages.
PHD (Doctor of Philosophy)
Salmonella, SseJ, Cholesterol, SPI-2, ABCA1, FAK