Loss of CNF_Y toxin-induced inflammation drives <i>Yersinia pseudotuberculosis</i> into persistency

Gastrointestinal infections caused by enteric yersiniae can become persistent and complicated by relapsing enteritis and severe autoimmune disorders. To establish a persistent infection, the bacteria have to cope with hostile surroundings when they transmigrate through the intestinal epithelium and colonize underlying gut-associated lymphatic tissues. How the bacteria gain a foothold in the face of host immune responses is poorly understood. Here, we show that the CNFY toxin, which enhances translocation of the antiphagocytic Yop effectors, induces inflammatory responses. This results in extensive tissue destruction, alteration of the intestinal microbiota and bacterial clearance. Suppression of CNFY function, however, increases interferon-γ-mediated responses, comprising non-inflammatory antimicrobial activities and tolerogenesis. This process is accompanied by a preterm reprogramming of the pathogen's transcriptional response towards persistence, which gives the bacteria a fitness edge against host responses and facilitates establishment of a commensal-type life style.由肠道耶尔森菌（enteric yersiniae）引发的胃肠道感染可进展为持续性感染，并可并发复发性肠炎与严重自身免疫性疾病。为建立持续性感染，该细菌需在穿越肠上皮（intestinal epithelium）并定植于下游肠道相关淋巴组织（gut-associated lymphatic tissues）的过程中，应对不利环境。目前学界对于该细菌如何在宿主免疫应答（immune responses）的压力下成功定植的机制仍知之甚少。本研究证实，可增强抗吞噬Yop效应蛋白（antiphagocytic Yop effectors）转位过程的CNFY毒素（CNFY toxin）能够诱导炎症反应（inflammatory responses）。该反应可引发广泛的组织损伤、肠道菌群（intestinal microbiota）失衡以及细菌清除（bacterial clearance）。然而，抑制CNFY毒素的功能，则会增强干扰素-γ（interferon-γ）介导的免疫应答，该应答涵盖非炎症性抗菌活性（non-inflammatory antimicrobial activities）与免疫耐受（tolerogenesis）过程。这一过程伴随病原体的转录应答（transcriptional response）提前重编程，使其朝向持续性感染的状态转变，从而赋予细菌对抗宿主免疫应答的生存优势，并助力其建立共生型生活方式（commensal-type life style）。