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Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus.
Proc Natl Acad Sci U S A. 2014 Aug 26; 111(34):12516-21.PN

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+Show Affiliations

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455;Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065;Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455;Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065;Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065;Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065;Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27559; and.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.Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455; lifang@umn.edu sjiang@nybloodcenter.org.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

25114257

Citation

Yang, Yang, et al. "Receptor Usage and Cell Entry of Bat Coronavirus HKU4 Provide Insight Into Bat-to-human Transmission of MERS Coronavirus." Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 34, 2014, pp. 12516-21.
Yang Y, Du L, Liu C, et al. Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus. Proc Natl Acad Sci U S A. 2014;111(34):12516-21.
Yang, Y., Du, L., Liu, C., Wang, L., Ma, C., Tang, J., Baric, R. S., Jiang, S., & Li, F. (2014). Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus. Proceedings of the National Academy of Sciences of the United States of America, 111(34), 12516-21. https://doi.org/10.1073/pnas.1405889111
Yang Y, et al. Receptor Usage and Cell Entry of Bat Coronavirus HKU4 Provide Insight Into Bat-to-human Transmission of MERS Coronavirus. Proc Natl Acad Sci U S A. 2014 Aug 26;111(34):12516-21. PubMed PMID: 25114257.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus. AU - Yang,Yang, AU - Du,Lanying, AU - Liu,Chang, AU - Wang,Lili, AU - Ma,Cuiqing, AU - Tang,Jian, AU - Baric,Ralph S, AU - Jiang,Shibo, AU - Li,Fang, Y1 - 2014/08/11/ PY - 2014/8/13/entrez PY - 2014/8/13/pubmed PY - 2014/12/15/medline SP - 12516 EP - 21 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 111 IS - 34 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/25114257/Receptor_usage_and_cell_entry_of_bat_coronavirus_HKU4_provide_insight_into_bat_to_human_transmission_of_MERS_coronavirus_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=25114257 DB - PRIME DP - Unbound Medicine ER -