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Manganese Mediates Its Antiviral Functions in a cGAS-STING Pathway Independent Manner.

ABSTRACT: The innate immune system is the first line of host defense sensing viral infection. Manganese (Mn) has recently been found to be involved in the activation of the innate immune DNA-sensing cGAS-STING pathway and subsequent anti-DNA virus function. However, it is still unclear whether Mn²⁺ mediates host defense against RNA viruses. In this study, we demonstrate that Mn²⁺ exhibited antiviral effects against various animal and human viruses, including RNA viruses such as PRRSVs and VSV, as well as DNA viruses such as HSV1, in a dose-dependent manner. Moreover, cGAS and STING were both investigated in the Mn²⁺ mediated antiviral roles using the knockout cells made by the CRISPR-Cas9 approach. Unexpectedly, the results revealed that neither cGAS knockout nor STING knockout had any effect on Mn²⁺-mediated antiviral functions. Nevertheless, we verified that Mn²⁺ promoted the activation of the cGAS-STING signaling pathway. These findings suggest that Mn²⁺ has broad-spectrum antiviral activities in a cGAS-STING pathway independent manner. This study also provides significant insights into redundant mechanisms participating in the Mn²⁺ antiviral functions, and also indicates a new target for Mn²⁺ antiviral therapeutics.

SUBMITTER: Sun S

PROVIDER: S-EPMC10058264 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Manganese Mediates Its Antiviral Functions in a cGAS-STING Pathway Independent Manner.

Sun Shaohua S Xu Yulin Y Qiu Ming M Jiang Sen S Cao Qi Q Luo Jia J Zhang Tangjie T Chen Nanhua N Zheng Wanglong W Meurens Francois F Liu Zongping Z Zhu Jianzhong J

Viruses 20230228 3

The innate immune system is the first line of host defense sensing viral infection. Manganese (Mn) has recently been found to be involved in the activation of the innate immune DNA-sensing cGAS-STING pathway and subsequent anti-DNA virus function. However, it is still unclear whether Mn<sup>2+</sup> mediates host defense against RNA viruses. In this study, we demonstrate that Mn<sup>2+</sup> exhibited antiviral effects against various animal and human viruses, including RNA viruses such as PRRSV ...[more]

PMID: 36992355

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Project description: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.

Dataset Information

Manganese Mediates Its Antiviral Functions in a cGAS-STING Pathway Independent Manner.

Publications

Manganese Mediates Its Antiviral Functions in a cGAS-STING Pathway Independent Manner.

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