Methylthioadenosine reduces host inflammatory response by suppressingSalmonellavirulence

Abstract

AbstractIn order to deploy virulence factors at appropriate times and locations, microbes must rapidly sense and respond to various metabolite signals. Previously we showed transient elevation of the methionine-derived metabolite methylthioadenosine (MTA) in serum during systemicSalmonella entericaserovar Typhimurium (S.Typhimurium) infection. Here we explored the functional consequences of increased MTA concentrations onS.Typhimurium virulence. We found that MTA—but not other related metabolites involved in polyamine synthesis and methionine salvage—reduced motility, host cell pyroptosis, and cellular invasion. Further, we developed a genetic model of increased bacterial endogenous MTA production by knocking out the master repressor of the methionine regulon,metJ. Like MTA treatedS.Typhimurium, the ΔmetJmutant displayed reduced motility, host cell pyroptosis, and invasion. These phenotypic effects of MTA correlated with suppression of flagellar andSalmonellapathogenicity island-1 (SPI-1) networks. ΔmetJ S.Typhimurium had reduced virulence in oral infection of C57BL/6 mice. Finally, ΔmetJbacteria induced a less severe inflammatory cytokine response in a mouse sepsis model. These data provide a possible bacterial mechanism for our previous findings that pretreating mice with MTA dampens inflammation and prolongs survival. Together, these data indicate that exposure ofS.Typhimurium to MTA or disruption of the bacterial methionine metabolism pathway is sufficient to suppress SPI-1 mediated processes, motility, andin vivovirulence.SignificanceSalmonella entericaserovar Typhimurium (S. Typhimurium) is a leading cause of gastroenteritis and bacteremia worldwide. Widespread multi-drug resistance, inadequate diagnostics, and the absence of a vaccine for use in humans, all contribute to the global burden of morbidity and mortality associated withS.Typhimurium infection. Here we find that increasing the concentration of the methionine derived metabolite methylthioadenosine, either inS.Typhimurium or in its environment, is sufficient to suppress virulence processes. These findings could be leveraged to inform future therapeutic interventions againstS.Typhimurium aimed at manipulating either host or pathogen methylthioadenosine production.