Sun Hui, Kamanova Jana, Lara-Tejero Maria, Galán Jorge E
Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, Connecticut, United States of America.
PLoS Pathog. 2016 Mar 2;12(3):e1005484. doi: 10.1371/journal.ppat.1005484. eCollection 2016 Mar.
Microbial infections usually lead to host innate immune responses and inflammation. These responses most often limit pathogen replication although they can also result in host-tissue damage. The enteropathogenic bacteria Salmonella Typhimurium utilizes a type III secretion system to induce intestinal inflammation by delivering specific effector proteins that stimulate signal transduction pathways resulting in the production of pro-inflammatory cytokines. We show here that a family of related Salmonella Typhimurium effector proteins PipA, GogA and GtgA redundantly target components of the NF-κB signaling pathway to inhibit transcriptional responses leading to inflammation. We show that these effector proteins are proteases that cleave both the RelA (p65) and RelB transcription factors but do not target p100 (NF-κB2) or p105 (NF-κB1). A Salmonella Typhimurium strain lacking these effectors showed increased ability to stimulate NF-κB and increased virulence in an animal model of infection. These results indicate that bacterial pathogens can evolve determinants to preserve host homeostasis and that those determinants can reduce the pathogen's virulence.
微生物感染通常会引发宿主的固有免疫反应和炎症。这些反应大多能限制病原体的复制，不过它们也可能导致宿主组织损伤。肠道致病菌鼠伤寒沙门氏菌利用III型分泌系统，通过递送特定效应蛋白来诱导肠道炎症，这些效应蛋白会刺激信号转导通路，从而产生促炎细胞因子。我们在此表明，一组相关的鼠伤寒沙门氏菌效应蛋白PipA、GogA和GtgA会冗余靶向NF-κB信号通路的组分，以抑制导致炎症的转录反应。我们发现这些效应蛋白是蛋白酶，它们能切割RelA（p65）和RelB转录因子，但不靶向p100（NF-κB2）或p105（NF-κB1）。一株缺失这些效应蛋白的鼠伤寒沙门氏菌在感染动物模型中显示出更强的刺激NF-κB的能力以及更高的毒力。这些结果表明，细菌病原体能够进化出决定因素来维持宿主内环境稳定，并且这些决定因素可能会降低病原体的毒力。
