Methylthioadenosine Suppresses Salmonella Virulence

<jats:title>ABSTRACT</jats:title> <jats:p>In order to deploy virulence factors at appropriate times and locations, microbes must rapidly sense and respond to various metabolite signals. Previously, we showed a transient elevation of the methionine-derived metabolite methylthioadenosine (MTA) concentration in serum during systemic <jats:named-content content-type="genus-species">Salmonella enterica</jats:named-content> serovar Typhimurium infection. Here we explored the functional consequences of increased MTA concentrations on <jats:italic>S</jats:italic>. 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, <jats:italic>metJ</jats:italic>. Like MTA-treated <jats:italic>S</jats:italic>. Typhimurium, the Δ<jats:italic>metJ</jats:italic> mutant displayed reduced motility, host cell pyroptosis, and invasion. These phenotypic effects of MTA correlated with suppression of flagellar and <jats:named-content content-type="genus-species">Salmonella</jats:named-content> pathogenicity island 1 (SPI-1) networks. <jats:italic>S</jats:italic>. Typhimurium Δ<jats:italic>metJ</jats:italic> had reduced virulence in oral and intraperitoneal infection of C57BL/6J mice independently of the effects of MTA on SPI-1. Finally, Δ<jats:italic>metJ</jats:italic> bacteria induced a less severe inflammatory cytokine response in a mouse sepsis model. Together, these data indicate that exposure of <jats:italic>S</jats:italic>. Typhimurium to MTA or disruption of the bacterial methionine metabolism pathway suppresses <jats:italic>S</jats:italic>. Typhimurium virulence.</jats:p>