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Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12516-21. doi: 10.1073/pnas.1405889111. Epub 2014 Aug 11.

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

Author information

1
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455;
2
Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065;
3
Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27559; and.
4
Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065; Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai 200032, China lifang@umn.edu sjiang@nybloodcenter.org.
5
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455; lifang@umn.edu sjiang@nybloodcenter.org.

Abstract

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.

PMID:
25114257
PMCID:
PMC4151778
DOI:
10.1073/pnas.1405889111
[Indexed for MEDLINE]
Free PMC Article
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