cGAS exacerbates Schistosoma japonicum infection in a STING-type I IFN-dependent and independent manner.
cGAS exacerbates Schistosoma japonicum infection in a STING-type I IFN-dependent and independent manner.
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cGAS 以 STING I 型 IFN 依赖性和独立方式加剧日本血吸虫感染
DOI：
10.1371/journal.ppat.1010233
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发表时间：
2022-03
期刊：
影响因子：
6.7
通讯作者：
Cao J
中科院分区：
文献类型：
--
作者：
Liang L;Shen Y;Hu Y;Liu H;Cao J
血吸虫病是由血吸虫属感染引起的，其特征在于响应于卵沉积的肉芽肿和纤维化。模式识别受体对于感知入侵的血吸虫、触发先天免疫应答和随后形成适应性免疫是重要的。环GMP-AMP合酶（cGAS）被鉴定为主要的胞质DNA传感器，其催化环GMP-AMP（cGAMP）的形成，环GMP-AMP（cGAMP）是激活干扰素基因的衔接蛋白刺激物（STING）的关键第二信使。STING与cGAMP的结合导致TANK结合激酶1（TBK 1）、干扰素调节因子3（IRF 3）的激活，以及随后的I型干扰素（IFN）应答。cGAS被建议调节感染性疾病、自身免疫性疾病和癌症。然而，cGAS在蠕虫感染中的功能尚不清楚。在这项研究中，我们发现Cgas缺乏增强了感染S.日本血吸虫，而不影响肝脏中的卵负荷。因此，Cgas缺失减轻了肝脏病理损伤，减少了虫卵肉芽肿的形成，并降低了纤维化的严重程度。相比之下，Sting缺失显著减少虫卵肉芽肿的形成，但不减少肝纤维化。值得注意的是，Cgas或Sting缺陷显著降低了感染S.山茱萸有趣的是，静脉注射重组IFNβ加重了肝损伤，促进了虫卵肉芽肿的形成，而不影响肝纤维化。氯膦酸盐脂质体介导的巨噬细胞耗竭表明，巨噬细胞是主要类型的细胞，有助于诱导的I型IFN反应在溶酶体感染。此外，cGAS对于I型IFN产生以及响应于S.日本血吸虫卵或成虫来源的DNA在巨噬细胞中。我们的结果阐明了cGAS在S.日本血吸虫感染，涉及感应核糖体衍生的DNA和产生I型IFN。此外，我们发现cGAS以STING型I-IFN-独立的方式调节肝纤维化。
Schistosomiasis, which is caused by infection with Schistosoma spp., is characterized by granuloma and fibrosis in response to egg deposition. Pattern recognition receptors are important to sense invading Schistosoma, triggering an innate immune response, and subsequently shaping adaptive immunity. Cyclic GMP-AMP synthase (cGAS) was identified as a major cytosolic DNA sensor, which catalyzes the formation of cyclic GMP-AMP (cGAMP), a critical second messenger for the activation of the adaptor protein stimulator of interferon genes (STING). The engagement of STING by cGAMP leads to the activation of TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), and the subsequent type I interferon (IFN) response. cGAS is suggested to regulate infectious diseases, autoimmune diseases, and cancer. However, the function of cGAS in helminth infection is unclear. In this study, we found that Cgas deficiency enhanced the survival of mice infected with S. japonicum markedly, without affecting the egg load in the liver. Consistently, Cgas deletion alleviated liver pathological impairment, reduced egg granuloma formation, and decreased fibrosis severity. In contrast, Sting deletion reduced the formation of egg granulomas markedly, but not liver fibrosis. Notably, Cgas or Sting deficiency reduced the production of IFNβ drastically in mice infected with S. japonicum. Intriguingly, intravenous administration of recombinant IFNβ exacerbated liver damage and promoted egg granuloma formation, without affecting liver fibrosis. Clodronate liposome-mediated depletion of macrophages indicated that macrophages are the major type of cells contributing to the induction of the type I IFN response during schistosome infection. Moreover, cGAS is important for type I IFN production and phosphorylation of TBK1 and IRF3 in response to stimulation with S. japonicum egg- or adult worm-derived DNA in macrophages. Our results clarified the immunomodulatory effect of cGAS in the regulation of liver granuloma formation during S. japonicum infection, involving sensing schistosome-derived DNA and producing type I IFN. Additionally, we showed that cGAS regulates liver fibrosis in a STING-type I–IFN-independent manner.