Regulation of Autophagy and Inflammasome by Statins---The Potential Alternative Therapy for Salmonella Infection

Salmonella spp. remain major public health problems for the whole world. The incidence of food-borne human infections caused by multi-drug-resistant strains of S. typhimurium increased substantially during 20th century with similar trends being reported from Europe and Taiwan. A better understanding of host-pathogen interactions in Salmonella infection is a prerequisite for the design of improved intervention strategies that could reduce the use of antimicrobial agents and multi-drug-resistant Salmonellosis. The autophagy and inflammasome pathways are ancient innate immune mechanisms for controlling invading pathogens. Recent evidence suggests that innate immunity of the host detects and defenses against Salmonella through the activation of autophagy and inflammasomes. From this-year project, we have observed the interaction between autophagy and inflammasome in Salmonella colitis mice model. Statins are cholesterol-lowering drugs, thereby reducing the risk of coronary disorders and hypercholesterolemia. However, patients receiving statin therapy experience reduced infection-associated mortality due to pneumonia, bacteremia , sepsis or multiple organ dysfunction syndrome. A retrospective case–control study conducted in three hospitals included all hospitalized patients diagnosed with Clostridium difficile associated diarrhoea revealed that statin use may provide protection against CDAD. Even more, current evidence from both observational studies and basic research suggests that statin therapy might be associated with a lower incidence of sepsis and a reduction in sepsis-related mortality. Recently, we demonstrated that disruption of membrane cholesterol recruited NOD2 into membrane, in one way, to suppress the PI3K/Akt-mediated anti-apoptotic responses, resulting in damaged Salmonella-containing vesicle (SCV); and in another way, to enhance Atg16L1 expression, leading to autophagic clearance of the damaged SCV (FC Huang, Int Mol Sci 2014). To our knowledge, there is no report how statins act on the innate immunity to control Salmonella infection via autophagy and inflammasome. Collectively, we hypothesize drugs lowering cholesterol may have therapeutic potential on Salmonella infection via regulation of autophagy and inflammasome. Therefore, the aims of the project are: (the first year) to study the regulation of Salmonella-induced autophagy and inflammasome in intestinal epithelial cells or macrophage by statins (In vitro study); (the second year) to investigate the potential therapy of statins in local Salmonella infection ( colitis) via regulation of autophagy in mucosal epithelial cells and inflammasomes in intestinal macrophages.; and (the third year) to investigate the potential therapy of statins in systemic Salmonella infection via regulation of inflammasomes in peripheral macrophages.

Project ID:PC10408-2134
External Project ID:MOST104-2314-B182-057