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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 Salmonella enterica serovar Typhimurium infection. Here we explored the functional consequences of increased MTA concentrations on S 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-treated S Typhimurium, the ΔmetJ mutant displayed reduced motility, host cell pyroptosis, and invasion. These phenotypic effects of MTA correlated with suppression of flagellar and Salmonella pathogenicity island 1 (SPI-1) networks. S Typhimurium ΔmetJ had reduced virulence in oral and intraperitoneal infection of C57BL/6J mice independently of the effects of MTA on SPI-1. Finally, ΔmetJ bacteria induced a less severe inflammatory cytokine response in a mouse sepsis model. Together, these data indicate that exposure of S Typhimurium to MTA or disruption of the bacterial methionine metabolism pathway suppresses S Typhimurium virulence.

Original publication

DOI

10.1128/IAI.00429-18

Type

Journal article

Journal

Infect Immun

Publication Date

09/2018

Volume

86

Keywords

SPI-1, Salmonella, flagellar motility, inflammation, metJ, metabolism, methionine salvage, methylthioadenosine, virulence regulation, Adenosine, Animals, Bacterial Proteins, Disease Models, Animal, Flagella, Gene Expression Regulation, Bacterial, Genomic Islands, Methionine, Mice, Mice, Inbred C57BL, Polyamines, Repressor Proteins, Salmonella Infections, Animal, Salmonella typhimurium, Virulence, Virulence Factors