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

Jiang, Yuting; Zhao, Guangyu; Song, Nianping; Li, Pei; Chen, Yuehong; Guo, Yan; Li, Junfeng; Du, Lanying; Jiang, Shibo; Guo, Renfeng; Sun, Shihui; Zhou, Yusen

C5a is an important proinflammatory polypeptide that mediates strong proinflammatory and immune modulatory signals in many diseases. For example, C5a induces the expression of IL-1 and IL-8 in mononuclear cells in vitro, and it enhances the release of IL-6 and TNF-α in vivo 23 . In this study, aberrant complement activation was confirmed in the lung tissues of mice after MERS-CoV infection, which prompted us to investigate the contribution of complement in the outcome of MERS-CoV infection. As expected, by blocking the C5a-C5aR axis, lung injury was alleviated after MERS-CoV infection, with less tissue damage accompanied by decreased infiltration of lung tissue macrophages and decreased Fig. 4 Alleviation of lung damage in hDPP4-transgenic mice after C5a-C5aR blockade. a-f Hematoxylin and eosin (H&E) staining of lung tissue sections obtained 7 days after anti-C5aR Ab treatment. Lung tissues in the sham treatment group presented mild to severe interstitial pneumonia, whereas those in the treatment group were less severe, with only mild focal thickening of alveolar septa. g Semi-quantitative histopathological analysis of H&E-stained lung sections 7 days after challenge. *P < 0.05 (Student's ttest with Welch's correction). h-i Body weight and survival rate after challenge. An additional six mice in each group were weighed and monitored. The experiment was repeated once and data from one representative experiment of these two experiments is presented systemic inflammatory response, especially the Th1 immune response as detected by IL-12 levels in sera. Previous studies based on infected human macrophages and dendritic cells indicated that MERS-CoV significantly induced the expression of inflammatory and chemotactic cytokines, as well as chemokines such as IP-10, MCP-1, IL-8, and IL-12 in macrophages and dendritic cells 10, 37, 38 . The host immune response triggered by MERS-CoV infection is a double-edged sword. It may help to suppress viral infection, but can cause severe lung damage as shown in this study. Importantly, we determined that blockade of the C5a-C5aR interaction by an anti-C5aR Ab could significantly reduce alveolar macrophage infiltration and IFN-γ receptor expression in lung tissue, resulting in alleviation of tissue damage induced by the excessive immune response.