衣原体是专性的细胞内细菌病原体,其可通过诱导破坏性宿主免疫应答而引起生殖器病理学。人类适应沙眼衣原体在人类宿主中引起炎症性疾病,但在小鼠中很容易被清除,和小鼠适应的鼠衣原体在鼠宿主中建立了生产性和致病性感染。虽然已经在小鼠和人类中发现了许多抗衣原体宿主抗性因子,对于独立于宿主抵抗力促进宿主适应性的宿主因素知之甚少。这里,我们表明,干扰素诱导的免疫相关的GTP酶M(Irgm)蛋白的功能作为这样的宿主因子改善感染相关的后遗症在小鼠女性生殖道,从而表征Irgm蛋白作为疾病耐受性的介质。具体来说,我们证明了所有三种鼠Irgm同源物(pan-Irgm-/-)缺陷的小鼠对沙眼衣原体的细胞自主免疫缺陷,这与细菌负荷的早期和短暂增加以及体内持续的炎症过度相关。相比之下,在用C.muridarum感染pan-Irgm-/-小鼠后,细菌负担不受影响,然而,生殖器炎症和疤痕病理仍在增加,证明Irgm蛋白可以在不改变细菌负担的情况下促进宿主的健康。此外,泛Irgm-/-小鼠在生殖器衣原体感染中显示肉芽肿性炎症增加,提示Irgm蛋白在肉芽肿形成和维持的调节中。这些发现表明,Irgm蛋白在体内调节对衣原体感染的致病性免疫反应,建立有效的感染模型来检测Irgm蛋白的免疫调节功能和机制。
目的:针对生殖器衣原体感染,免疫系统启动促炎反应来抵抗病原体,然而,必须严格控制炎症,以避免对宿主生殖器组织的附带损害和疤痕。人IRGM基因的变异与自身炎性疾病的易感性有关,但其在改善由感染引起的炎性疾病中的作用尚不清楚。这里,我们使用缺乏所有三种鼠Irgm同源物的小鼠来证明Irgm蛋白不仅提供宿主对衣原体感染的抗性,而且限制女性生殖道的相关炎症。特别是,我们发现鼠Irgm表达可以预防肉芽肿性炎症,与人IRGM变异相关的炎性疾病平行。因此,我们的发现将生殖器衣原体感染确立为研究Irgm蛋白在促进保护性免疫和限制致病性炎症中的作用的有用模型。
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.
OBJECTIVE: In response to genital Chlamydia infection, the immune system mounts a proinflammatory response to resist the pathogen, yet inflammation must be tightly controlled to avoid collateral damage and scarring to host genital tissue. Variation in the human IRGM gene is associated with susceptibility to autoinflammatory diseases but its role in ameliorating inflammatory diseases caused by infections is poorly defined. Here, we use mice deficient for all three murine Irgm paralogs to demonstrate that Irgm proteins not only provide host resistance to Chlamydia infections but also limit associated inflammation in the female genital tract. In particular, we find that murine Irgm expression prevents granulomatous inflammation, which parallels inflammatory diseases associated with variants in human IRGM. Our findings therefore establish genital Chlamydia infection as a useful model to study the roles for Irgm proteins in both promoting protective immunity and limiting pathogenic inflammation.