Data from: Irgm proteins attenuate inflammatory disease in mouse models of genital Chlamydia infection

Chlamydiae are obligate intracellular bacterial pathogens that may cause genital pathology via induction of destructive host immune responses. Human-adapted Chlamydia trachomatis causes inflammatory disease in human hosts but is easily cleared in mice, and mouse-adapted Chlamydia muridarum establishes a productive and pathogenic infection in murine hosts. While numerous anti-chlamydial host resistance factors have been discovered in mice and humans alike, little is known about host factors promoting host fitness independent of host resistance. Here, we show that interferon-inducible immunity-related GTPase M (Irgm) proteins function as such host factors ameliorating infection-associated sequalae in the murine female genital tract, thus characterizing Irgm proteins as mediators of disease tolerance. Specifically, we demonstrate that mice deficient for all three murine Irgm paralogs (pan-Irgm−/−) are defective for cell-autonomous immunity to C. trachomatis, which correlates with an early and transient increase in bacterial burden and sustained hyperinflammation in vivo. In contrast, upon infection of pan-Irgm−/− mice with C. muridarum, bacterial burden is unaffected, yet genital inflammation and scarring pathology are nonetheless increased, demonstrating that Irgm proteins can promote host fitness without altering bacterial burden. Additionally, pan-Irgm−/− mice display increased granulomatous inflammation in genital Chlamydia infection, implicating Irgm proteins in the regulation of granuloma formation and maintenance. These findings demonstrate that Irgm proteins regulate pathogenic immune responses to Chlamydia infection in vivo, establishing an effective infection model to examine the immunoregulatory functions and mechanisms of Irgm proteins.

衣原体目（Chlamydiae）为专性胞内细菌病原体，可通过诱导破坏性宿主免疫应答引发生殖道病理损伤。适应人类的沙眼衣原体（Chlamydia trachomatis）可在人体宿主中引发炎症性疾病，但在小鼠体内易被清除；而适应小鼠的鼠衣原体（Chlamydia muridarum）则可在啮齿类宿主中建立可增殖且具有致病性的感染。尽管已在小鼠与人类体内发现多种抗衣原体宿主抗性因子，但对于不依赖宿主抗性、仅促进宿主健康的宿主因子，目前所知甚少。本研究表明，干扰素诱导免疫相关GTP酶M（Irgm）家族蛋白正是此类宿主因子，可缓解小鼠雌性生殖道的感染相关后遗症，从而将Irgm蛋白界定为疾病耐受的介导因子。具体而言，本研究证实，同时敲除小鼠全部3种Irgm旁系同源基因的小鼠（pan-Irgm−/−）在对抗沙眼衣原体感染时存在细胞自主免疫缺陷，这与体内细菌载量早期一过性升高及持续性过度炎症反应相关。与之相反，当全Irgm敲除小鼠感染鼠衣原体时，其细菌载量未受影响，但生殖道炎症与瘢痕病理却显著加重，这表明Irgm蛋白可在不改变细菌载量的前提下促进宿主健康。此外，全Irgm敲除小鼠在生殖道衣原体感染时表现出更为严重的肉芽肿性炎症，提示Irgm蛋白参与调控肉芽肿的形成与维持。上述研究结果证实，Irgm蛋白在体内可调控衣原体感染引发的致病性免疫应答，同时也为探究Irgm蛋白的免疫调节功能与作用机制提供了有效的感染模型。