Salmonella Activation of STAT3 Signaling by SarA Effector Promotes Intracellular Replication and Production of IL-10

Salmonella enterica is an important foodborne pathogen that uses secreted effector proteins to manipulate host pathways to facilitate survival and dissemination. Different S. enterica serovars cause disease syndromes ranging from gastroenteritis to typhoid fever and vary in their effector repertoire. We leveraged this natural diversity to identify stm2585, here designated sarA (Salmonella anti-inflammatory response activator), as a Salmonella effector that induces production of the anti-inflammatory cytokine IL-10. RNA-seq of cells infected with either ΔsarA or wild-type S. Typhimurium revealed that SarA activates STAT3 transcriptional targets. Consistent with this, SarA is necessary and sufficient for STAT3 phosphorylation, STAT3 inhibition blocks IL-10 production, and SarA and STAT3 interact by co-immunoprecipitation. These effects of SarA contribute to intracellular replication in vitro and bacterial load at systemic sites in mice. Our results demonstrate the power of using comparative genomics for identifying effectors and that Salmonella has evolved mechanisms for activating an important anti-inflammatory pathway. [Display omitted] •SarA (Salmonella anti-inflammatory response activator) effector induces IL-10•SarA activates an anti-inflammatory STAT3 transcriptional program•SarA contributes to Salmonella intracellular replication and virulence in mice•Variable presence in strains facilitated SarA identification, suggests adaptation Salmonella has evolved a diverse repertoire of secreted effectors that manipulate host physiology. Here, Jaslow et al. leverage natural genetic diversity to reveal the SarA (Salmonella anti-inflammatory response activator) effector. SarA activates the transcription factor STAT3 to induce production of the anti-inflammatory cytokine IL-10, promote intracellular replication, and increase virulence.