Malarial Parasite Infection Compromises Gastrointestinal Defenses Against Enteric Pathogens

Though generally associated with the etiology of gastroenteritis, non-typhoidal Salmonella (NTS) serovars such as Salmonella enterica serovar Typhimurium are also frequently linked to disseminated infections in sub-Saharan Africa, commonly referred to as invasive NTS disease (iNTS). Epidemiological evidence has identified malaria in children as a significant risk factor for the development of iNTS. Prior studies discovered that Plasmodium infections in mice can transiently alter the commensal microbial flora and increase the initial colonization of enteric S. Typhimurium infections. In order to better understand how malaria impacts susceptibility to enteric pathogens, I further assessed the effects of Plasmodium yoelii infection on the mouse intestine. Although my studies confirmed that P. yoelii infection could impact the gut microbiota, changes in abundance of microbial taxa were not obviously correlated with increasing implantation levels of S. Typhimurium. Rather, P. yoelii was found to induce hypochlorhydria dependent on TNF-α signaling that impairs gastric defense against orally inoculated S. Typhimurium. Additionally, my investigation found that levels of endogenous Enterobacteriaceae, particularly Escherichia coli, consistently increase in the intestines during P. yoelii infection. Neither reduction in gastric acid alone nor E. coli utilization of increased levels of inflammation-associated nitrate could explain the bloom. However, a similar outgrowth of intestinally colonized avirulent S. Typhimurium was dependent on acrAB, vital components of a multidrug efflux pump (AcrAB-TolC) common to Enterobacteriaceae that is known to provide bile acid resistance. I determined that both P. yoelii infection and induction of hemolysis alone impacted the intestinal bile composition, and phenylhydrazine-induced hemolysis was sufficient to stimulate the E. coli expansion. The hemolysis-associated E. coli bloom was also dependent on functional siderophore uptake systems, as a tonB mutant did not expand and was outcompeted by wildtype E. coli in mice that were treated with phenylhydrazine. Together, these data suggest that both hemolysis-associated shifts in the gut metabolome and the immune response to the Plasmodium parasite contribute to enhanced susceptibility to S. Typhimurium implantation and colonization. My work highlights the critical role of oft-overlooked non-immunological antibacterial defenses in resisting enteric colonization and illustrates how Plasmodium can impact unexpected aspects of physiology that influence susceptibility to secondary infections