A Dual Role of Complement Activation in the Development of Fulminant Hepatic Failure Induced by Murine-Beta-Coronavirus Infection

Frontiers in Cellular and Infection Microbiology

Yujun Cui¹  Yingying Fang¹  Guangyu Zhao¹  Binhui Yang²  Min Li²  Yuting Jiang²  Yan Guo²  Xuelian Han²  Tongtong Gao²  Wei Xue²  Shihui Sun² 

[1] School of Basic Medical Sciences, Anhui Medical University, Hefei, China;State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China;

关键词: betacoronavirus;    MHV-3;    complement;    FHF;    SARS-CoV-2;    animal model;   

DOI  :  10.3389/fcimb.2022.880915

来源: DOAJ

【 摘 要 】

With the epidemic of betacoronavirus increasing frequently, it poses a great threat to human public health. Therefore, the research on the pathogenic mechanism of betacoronavirus is becoming greatly important. Murine hepatitis virus strain-3 (MHV-3) is a strain of betacoronavirus which cause tissue damage especially fulminant hepatic failure (FHF) in mice, and is commonly used to establish models of acute liver injury. Recently, MHV-3-infected mice have also been introduced to a mouse model of COVID-19 that does not require a Biosafety Level 3 (BSL-3) facility. FHF induced by MHV-3 is a type of severe liver damage imbalanced by regenerative hepatocellular activity, which is related to numerous factors. The complement system plays an important role in host defense and inflammation and is involved in first-line immunity and/or pathogenesis of severe organ disorders. In this study, we investigated the role of aberrant complement activation in MHV-3 infection-induced FHF by strategies that use C3-deficient mice and intervene in the complement system. Our results showed that mice deficient in C3 had more severe liver damage, a higher viral load in the liver and higher serum concentrations of inflammatory cytokines than wild-type controls. Treatment of C57BL/6 mice with C3aR antagonist or anti-C5aR antibody reduced liver damage, viral load, and serum IFN-γ concentration compared with the control group. These findings indicated that complement system acts as a double-edged sword during acute MHV-3 infection. However, its dysregulated activation leads to sustained inflammatory responses and induces extensive liver damage. Collectively, by investigating the role of complement activation in MHV-3 infection, we can further understand the pathogenic mechanism of betacoronavirus, and appropriate regulation of immune responses by fine-tuning complement activation may be an intervention for the treatment of diseases induced by betacoronavirus infection.

【 授权许可】

Unknown