Blockade of the C5a–C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV

Abstract

The pathogenesis of highly pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV) remains poorly understood. In a previous study, we established an hDPP4-transgenic (hDPP4-Tg) mouse model in which MERS-CoV infection causes severe acute respiratory failure and high mortality accompanied by an elevated secretion of cytokines and chemokines. Since excessive complement activation is an important factor that contributes to acute lung injury after viral infection, in this study, we investigated the role of complement in MERS-CoV-induced lung damage. Our study showed that complement was excessively activated in MERS-CoV-infected hDPP4-Tg mice through observations of increased concentrations of the C5a and C5b-9 complement activation products in sera and lung tissues, respectively. Interestingly, blocking C5a production by targeting its receptor, C5aR, alleviated lung and spleen tissue damage and reduced inflammatory responses. More importantly, anti-C5aR antibody treatment led to decreased viral replication in lung tissues. Furthermore, compared with the sham treatment control, apoptosis of splenic cells was less pronounced in the splenic white pulp of treated mice, and greater number of proliferating splenic cells, particularly in the red pulp, was observed. These data indicate that (1) dysregulated host immune responses contribute to the severe outcome of MERS; (2) excessive complement activation, triggered by MERS-CoV infection, promote such dysregulation; and (3) blockade of the C5a–C5aR axis lead to the decreased tissue damage induced by MERS-CoV infection, as manifested by reduced apoptosis and T cell regeneration in the spleen. Therefore, the results of this study suggest a new strategy for clinical intervention and adjunctive treatment in MERS-CoV cases.

These authors contributed equally: Yuting Jiang, Guangyu Zhao.

These authors contributed equally: Yuting Jiang, Guangyu Zhao.

Acknowledgements

This study was supported by grants from the National Key Plan for Scientific Research and Development of China (2016YFD0500306), the National Natural Science Foundation of China (81571983), the National Key Research and Development Program of China (2016YFC1202903), the National Project of Infectious Diseases (2017ZX10304402-003), BWS14J058, and 16CXZ039.

Conflict of interest

The authors declare that they have no conflict of interest.