Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 34; pp. 12516 - 12521
• Main Authors: Yang, Yang, Du, Lanying, Liu, Chang, Wang, Lili, Ma, Cuiqing, Tang, Jian, Baric, Ralph S., Jiang, Shibo, Li, Fang
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26-08-2014; National Acad Sciences
• Subjects: Animals; Bats; Biological Sciences; Cell lines; Chiroptera - virology; Coronavirus; Coronavirus - classification; Coronavirus - pathogenicity; Coronavirus - physiology; Coronavirus Infections - transmission; Coronavirus Infections - virology; Dipeptidyl Peptidase 4 - physiology; Disease Reservoirs - virology; Disease transmission; Host Specificity; Host-Pathogen Interactions; Humans; Infections; Middle East; Proteases; Receptors; Receptors, Virus - physiology; Respiratory Tract Infections - transmission; Respiratory Tract Infections - virology; Retroviridae; SARS virus; Spike Glycoprotein, Coronavirus - physiology; Virulence; Virus Internalization; Viruses; Middle East
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1405889111

Middle East respiratory syndrome coronavirus (MERS-CoV) currently spreads in humans and causes ∼36% fatality in infected patients. Believed to have originated from bats, MERS-CoV is genetically related to bat coronaviruses HKU4 and HKU5. To understand how bat coronaviruses transmit to humans, we investigated the receptor usage and cell entry activity of the virus-surface spike proteins of HKU4 and HKU5. We found that dipeptidyl peptidase 4 (DPP4), the receptor for MERS-CoV, is also the receptor for HKU4, but not HKU5. Despite sharing a common receptor, MERS-CoV and HKU4 spikes demonstrated functional differences. First, whereas MERS-CoV prefers human DPP4 over bat DPP4 as its receptor, HKU4 shows the opposite trend. Second, in the absence of exogenous proteases, both MERS-CoV and HKU4 spikes mediate pseudovirus entry into bat cells, whereas only MERS-CoV spike, but not HKU4 spike, mediates pseudovirus entry into human cells. Thus, MERS-CoV, but not HKU4, has adapted to use human DPP4 and human cellular proteases for efficient human cell entry, contributing to the enhanced pathogenesis of MERS-CoV in humans. These results establish DPP4 as a functional receptor for HKU4 and host cellular proteases as a host range determinant for HKU4. They also suggest that DPP4-recognizing bat coronaviruses threaten human health because of their spikes’ capability to adapt to human cells for cross-species transmissions.