Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus
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. As of June 16, 2014, the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV) had infected 701 people, with a fatality rate of ∼36% (www.who.int/csr/don/2014_06_16_mers/en/), and had demonstrated the capability for human-to-human transmission (1, 2). Alarmingly, coronavirus surveillance studies have suggested that MERS-CoV originated from animals, with bats as the likely natural reservoir and camels as the likely intermediate hosts (3⇓⇓–6). Hence, cross-species transmission of MERS-CoV from bats to humans, either directly or through camels, poses a constant and long-term threat to human health.