Salmonella Activation of STAT3 Signaling by SarA Effector Promotes Intracellular Replication and Production of IL-10
Salmonella Activation of STAT3 Signaling by SarA Effector Promotes Intracellular Replication and Production of IL-10
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DOI：
10.1016/j.celrep.2018.05.072
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发表时间：
2018-06-19
期刊：
影响因子：
8.8
通讯作者：
Ko, Dennis C.
中科院分区：
文献类型：
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作者：
Jaslow, Sarah L.;Gibbs, Kyle D.;Ko, Dennis C.
肠道沙门氏菌是一种重要的食源性病原体，它利用分泌的效应蛋白操纵宿主途径以促进生存和传播。不同的S。肠道菌血清型引起从胃肠炎到伤寒的疾病综合征，并且在它们的效应子库中变化。我们利用这种天然多样性来鉴定stm 2585，这里指定为sarA（沙门氏菌抗炎反应激活剂），作为诱导抗炎细胞因子IL-10产生的沙门氏菌效应子。用AsarA或野生型S.鼠伤寒沙门氏菌显示，SarA激活STAT 3转录靶点。与此一致，Delta SarA对于STAT 3磷酸化是必要且充分的，STAT 3抑制会阻止IL-10的产生，并且SarA和STAT 3通过免疫共沉淀相互作用。SarA的这些作用有助于体外细胞内复制和小鼠全身部位的细菌负荷。我们的研究结果证明了使用比较基因组学来识别效应子的能力，并且沙门氏菌已经进化出激活重要抗炎途径的机制。
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 AsarA or wild-type S. Typhimurium revealed that SarA activates STAT3 transcriptional targets. Consistent with this, Delta 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.