Complement Receptor C5aR1 Inhibition Reduces Pyroptosis in hDPP4-Transgenic Mice Infected with MERS-CoV.

Yuting Jiang,Yusen Zhou,Guangyu Zhao,Jiangfan Li,Lei He,Guang Tian,Yan Guo,Shihui Sun,Yue Teng,Pei Li,Hong Sun,Yuehong Chen,Junfeng Li

doi:10.3390/v11010039

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic virus with a crude mortality rate of ~35%. Previously, we established a human DPP4 transgenic (hDPP4-Tg) mouse model in which we studied complement overactivation-induced immunopathogenesis. Here, to better understand the pathogenesis of MERS-CoV, we studied the role of pyroptosis in THP-1 cells and hDPP4 Tg mice with MERS-CoV infection. We found that MERS-CoV infection induced pyroptosis and over-activation of complement in human macrophages. The hDPP4-Tg mice infected with MERS-CoV overexpressed caspase-1 in the spleen and showed high IL-1β levels in serum, suggesting that pyroptosis occurred after infection. However, when the C5a-C5aR1 axis was blocked by an anti-C5aR1 antibody (Ab), expression of caspase-1 and IL-1β fell. These data indicate that MERS-CoV infection induces overactivation of complement, which may contribute to pyroptosis and inflammation. Pyroptosis and inflammation were suppressed by inhibiting C5aR1. These results will further our understanding of the pathogenesis of MERS-CoV infection.

Highlights

Middle East respiratory syndrome coronavirus (MERS-CoV), the second highly pathogenic coronavirus to emerge after severe acute respiratory syndrome coronavirus (SARS-CoV), causes severe acute respiratory failure and extra-pulmonary multi-organ damage accompanied by severe systemic inflammation [1,2,3]
In a previous study we demonstrated that aberrant complement activation contributes to severe outcomes in hDPP4 transgenic mice infected with MERS-CoV, and that preventing over-activation of the complement system may be an effective clinical therapy for MERS [16]
Unlike abortive infection of SARS-CoV in human macrophages, MERS-CoV can establish a productive infection in macrophages and induce production of proinflammatory cytokines and chemokines [18]

Summary

Introduction

Middle East respiratory syndrome coronavirus (MERS-CoV), the second highly pathogenic coronavirus to emerge after severe acute respiratory syndrome coronavirus (SARS-CoV), causes severe acute respiratory failure and extra-pulmonary multi-organ damage accompanied by severe systemic inflammation [1,2,3]. Complement activation and pyroptosis are two proteolytic cascades that defend the host against dangerous pathogens. They are important parts of the innate immune system and have some similar characteristics, including pore-formation and proinflammatory characteristics. Activation of caspase-1 relies on assembly of inflammasome complexes, which contain NLRP1b, NLRC4, NLRP3, and AIM2. Different inflammasomes are activated by different pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs)

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Conclusion