title: Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus.
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.
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455;
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065;
authors.forename: Lanying
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455;
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065;
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065;
authors.forename: Cuiqing
authors.initials: C
authors.lastname: Ma
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065;
authors.forename: Jian
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27559; and.
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Baric
authors.affiliation: 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.
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455; lifang@umn.edu sjiang@nybloodcenter.org.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
mesh_terms: D000818:Animals; D002685:Chiroptera / Q000821:virology*; D017934:Coronavirus / Q000145:classification / Q000472:pathogenicity* / Q000502:physiology*; D018352:Coronavirus Infections / Q000635:transmission* / Q000821:virology; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology; D004197:Disease Reservoirs / Q000821:virology; D058507:Host Specificity; D054884:Host-Pathogen Interactions; D006801:Humans; D008877:Middle East; D011991:Receptors, Virus / Q000502:physiology; D012141:Respiratory Tract Infections / Q000635:transmission / Q000821:virology; D064370:Spike Glycoprotein, Coronavirus / Q000502:physiology; D014774:Virulence; D053586:Virus Internalization
chemical_list: D011991:Receptors, Virus; D064370:Spike Glycoprotein, Coronavirus; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4
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