The innate immune system fights infection with inflammasomes and interferons. Facultative bacterial pathogens that inhabit the host cytosol avoid inflammasomes1-6 and are often insensitive to type I interferons (IFN-I), but are restricted by IFN-γ7-11. However, it remains unclear how obligate cytosolic bacterial pathogens, including Rickettsia species, interact with innate immunity. Here, we report that the human pathogen Rickettsia parkeri is sensitive to IFN-I and benefits from inflammasome-mediated host cell death that antagonizes IFN-I. R. parkeri-induced cell death requires the cytosolic lipopolysaccharide (LPS) receptor caspase-11 and antagonizes IFN-I production mediated by the DNA sensor cGAS. The restrictive effects of IFN-I require the interferon regulatory factor IRF5, which upregulates genes encoding guanylate-binding proteins (GBPs) and inducible nitric oxide synthase (iNOS), which we found to inhibit R. parkeri. Mice lacking both IFN-I and IFN-γ receptors succumb to R. parkeri, revealing critical and overlapping roles for these cytokines in vivo. The interactions of R. parkeri with inflammasomes and interferons are similar to those of viruses, which can exploit the inflammasome to avoid IFN-I12, are restricted by IFN-I via IRF513,14, and are controlled by IFN-I and IFN-γ in vivo15-17. Our results suggest that the innate immune response to an obligate cytosolic bacterial pathogen lies at the intersection of antibacterial and antiviral responses.

中文翻译：

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I型干扰素的炎性体介导的拮抗作用增强了立克次体的发病机理。

天生的免疫系统可以抵抗炎症小体和干扰素的感染。居住在宿主细胞质中的兼性细菌病原体可避免炎性体1-6，并且通常对I型干扰素（IFN-I）不敏感，但受到IFN-γ7-11的限制。但是，尚不清楚包括立克次体在内的胞质细菌病原体如何与先天免疫相互作用。在这里，我们报告人类病原体立克次体帕克（Rickettsia parkeri）对IFN-I敏感，并受益于拮抗IFN-IR帕克诱导的细胞死亡的炎性体介导的宿主细胞死亡，需要胞浆脂多糖（LPS）受体caspase-11并拮抗IFN-我的生产是由DNA传感器cGAS介导的。IFN-1的限制性作用需要干扰素调节因子IRF5，上调编码鸟苷酸结合蛋白（GBPs）和诱导型一氧化氮合酶（iNOS）的基因，我们发现它们抑制了R. parkeri。缺乏IFN-I和IFN-γ受体的小鼠都死于R. parkeri，在体内揭示了这些细胞因子的关键作用和重叠作用。R. parkeri与炎性体和干扰素的相互作用类似于病毒，它们可以利用炎性体避开IFN-I12，通过IRF513,14被IFN-I限制，并受IFN-I和IFN-γ的控制。在体内15-17。我们的结果表明，对专一的胞质细菌病原体的先天免疫应答位于抗菌和抗病毒应答的交叉点。揭示了这些细胞因子在体内的关键作用和重叠作用。R. parkeri与炎性体和干扰素的相互作用类似于病毒，它们可以利用炎性体避开IFN-I12，通过IRF513,14被IFN-I限制，并受IFN-I和IFN-γ的控制。在体内15-17。我们的结果表明，对专一的胞质细菌病原体的先天免疫应答位于抗菌和抗病毒应答的交叉点。揭示了这些细胞因子在体内的关键作用和重叠作用。R. parkeri与炎性体和干扰素的相互作用类似于病毒，它们可以利用炎性体避开IFN-I12，通过IRF513,14被IFN-I限制，并受IFN-I和IFN-γ的控制。在体内15-17。我们的结果表明，对专一的胞质细菌病原体的先天免疫应答位于抗菌和抗病毒应答的交叉点。