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

According to a comparative study of SARS-CoV patients and the limited clinical data of MERS-CoV patients, immune-mediated pathogenesis was proposed as a potential factors in the severe outcome of MERS-CoVinfected patients. In this study, a human DPP4 transgenic (hDDP4-Tg) mouse model we previously developed was used to investigate whether MERS-CoV infection can cause aberrant systemic inflammatory responses 27 . One may question whether the human DPP4 protein expressed in the Tg mouse itself may cause dysregulated immune and inflammatory responses since hDPP4 can function as a signaling protein on the surface of T cells, as an enzyme cleaving chemokines or cytokines in the lungs and brain, and a as costimulatory molecule for inducing cell proliferation 29 . However, in our previous study, we observed that the hDPP4-Tg and wild-type C57BL/6 mice had very similar presentations of immune responses without MERS-CoV infection (data not shown). In addition, Tseng's group did not observe dysregulated immune and inflammatory responses in the hDDP4-Tg mice before viral challenge 30 . Above all, these results suggested that the human DPP4 protein expressed in the TG mouse may not significantly influence immune and inflammatory responses in mice, possibly because of the differences in DPP4 between species. The results of this study confirm that aberrant systemic inflammatory responses, especially those mediated by the dysregulated complement system as induced by MERS-CoV infection, may contribute to the severe outcome of such infections. Furthermore, blocking the C5a-C5aR interaction and complement activation by blocking the C5a-C5aR axis could be a promising strategy for the adjunctive treatment of MERS-CoV infection.