DPP4-mediated MERS-CoV pathogenesis and the potential of the soluble DPP4 as a medical countermeasure against MERS infection

Abstract

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a newly emerged and highly pathogenic virus that was first discovered in Saudi Arabia in 2012. Since its emergence, MERS-CoV has caused more than 2450 human infections in twenty-seven countries around the world resulting in death in about 36% of the reported cases. MERS-CoV is spread widely in the dromedary camels of the Arabian Peninsula and parts of Africa, which are suspected to be the source of human infections. Due to this large zoonotic reservoir of the virus, the high mortality rate, and the proven transmissibility among humans, MERS-CoV represents a serious ongoing public health threat. This threat is further complicated by the absence of effective and FDA-approved medical countermeasures (MCMs) against this virus as well as the extremely limited information on its pathogenesis. Built upon our recent success in the development of a novel transgenic mouse model expressing human dipeptidyl peptidase 4 (DPP4), the entry receptor of MERS-CoV to the permissive hosts, I studied DPP4-mediated pathogenesis of MERS and explored the likelihood of using secreted/soluble human DPP4 molecules as a countermeasure for MERS. Using heterozygous (+/-) and homozygous (+/+) hDPP4 transgenic mice, I found that the elevated soluble human DPP4 expression enabled hDPP4+/+ Tg mice to be more resistant than their hDPP4+/- counterparts to MERS-CoV infection, likely via functioning as receptor decoys. However, my studies also revealed that the inherited increase of DPP4 expression enhances the innate immunity of hDPP4+/+ Tg mice to MERS-CoV infection. I also demonstrated that MERS-CoV infection significantly reduced the levels of sDPP4 in the circulation which might contribute to MERS pathogenesis, in part, by altering the host immune response. Lastly, we investigated the signature of the host antiviral responses and identified key innate antiviral genes critically involved in the host defense against acute MERS-CoV infection. These identified genes could be the targets of new host-directed drugs to treat acute viral infection. Taken together, my studies provide not only new insights into MERS-CoV pathogenesis and treatment but also attractive future directions for the development of new and effective drug against MERS and beyond.