Role of arginine as a metabolic cue during enteric infection - Project Summary: Even in a developed country such as the United States, Salmonella enterica serovar Typhimurium (STm) infects 1.35 million people every year. Infection with STm causes acute intestinal inflammation and the disease can progress to life-threatening bacteremia in vulnerable populations. Numerous factors, including host immune status, gut microbiome composition, and co-infections with other pathogens, influence the pathogenesis of STm. Gut microbiota-derived metabolites such as short-chain fatty acids and secondary bile acids also significantly impact STm infection. We recently discovered that arginine, a semi- essential amino acid, increases STm virulence and its dissemination to peripheral organs. Arginine availability in the gut lumen depends on the diet and contributions from the gut microbiota and the host. We uncovered an additional source in the gut: commensal fungi. We showed that Candida albicans, a fungus present in 60% of people, increases de novo biosynthesis of arginine in the presence of STm and release millimolar amounts of arginine in the extracellular environment. In addition, the frequent use of arginine as a dietary supplement to ameliorate cardiac health issues also influences arginine availability in the gut. STm is therefore likely to encounter varying amounts of arginine when infecting a human. However, there is a huge knowledge gap in understanding how gut arginine metabolism influences pathogenesis of enteric pathogens such as STm. The main goal of this proposal is to understand how arginine availability modulates the gut environment in a way that results in increased STm virulence. We hypothesize that an increase in arginine will increase Salmonella pathogenesis by two mechanisms: (Aim 1) direct utilization of arginine by STm, gut microbiota, and host and (Aim 2) modulation of the host immune response by arginine. In particular, in Aim 1, we will dissect the contributions of arginine utilization by determining whether STm arginine catabolism is required for its pathogenesis in vivo in the gut; by identifying if arginine opens the niche for arginine-utilizing gut microbiota that influence Salmonella pathogenesis; by determining if the host utilization of arginine contributes to the increased pathogenesis of Salmonella. In Aim 2, we will investigate how arginine influences the immune response to STm infection. Our preliminary data showed a dampening of the immune response during STm infection. We will characterize immune cell recruitment to the gut and establish an in vitro model recapitulating the blunted immune response to STm infection in the presence of arginine. We will further determine the molecular mechanism behind this modulation of the immune response. This proposal will be a foundational study to understand if similar mechanism exist for other enteric infections such as EHEC. Executing this research program at the University of Illinois at Chicago (UIC) will allow the candidate to establish as an independent researcher and securing a tenured faculty position at a major research institution.
