Recently, a novel and highly virulent Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV) emerged, causing ~40% mortality rates. MERS-CoV replicates efficiently in humans, camels and bats, but not mouse cells demonstrating a broad yet rodent-restricted host range. Ominously, person-to-person transmission and subclinical infections endanger global populations and economies. Importantly, we have demonstrated that closely related bat coronaviruses (Bt CoV), like HKU4, uses the same bat and human receptor for entry as MERS- CoV, raising the specter of further zoonotic introductions of antigenically distinct coronaviruses into human populations. Consequently, we develop a multidisciplinary program that includes X- Ray crystallography, electron microscopy, protein biochemistry, molecular virology, reverse genetics and animal model development to address fundamental questions regulating key BtCoV HKU4 and MERS-CoV-host structure-function relationships in: i) receptor mediated binding, fusion and entry, ii) cross species transmission, and iii) in vivo pathogenesis. MERS-CoV and BtCoV HKU4 encode an envelope-anchored spike glycoprotein (S) that binds to its host receptor dipeptidyl peptidase 4 (DPP4) through its S1 subunit, initiating a cascade of host serine protease regulated conformation changes that elicit S2-mediated membrane fusion and entry. The major barrier for HKU4 mediated entry into human cells occurs at protease initiated membrane fusion, rather than at the receptor binding interface. Thus, our program identifies a checkpoint associated with bat CoV cross species transmission into other mammals, including humans. In addition to identifying key structural and biochemical interactions that regulate S and DPP4 receptor ortholog-guided binding protease regulated fusion and entry, we apply reverse genetics, structure-guided mutations, and experimental evolution to study HKU4 and MERS-CoV host adaptation and pathogenesis, using recently developed transgenic animal models.
In Aim 1, we study the biochemistry and structure of MERS-CoV and HKU4 bound to various species receptor-binding domains (RBD).
In Aim 2, we study S processing by bat and human entry proteases.
In Aim 3, we study HKU4 and MERS-CoV pathogenesis using transgenic mice and experimental evolution. The overall goal is to build a comprehensive understanding of the molecular mechanisms guiding group 2c CoV receptor recognition, entry and pathogenesis. In parallel, we produce key deliverables that are crucial for developing effective antivirals and vaccines, thereby improving rapid response and the overall global health.

Public Health Relevance

MERS-CoV is an emerging respiratory virus associated with ~40% mortality rates in humans. Virus receptor interactions and S glycoprotein-protease processing events are key regulators of entry, tissue tropism, species specificity and disease emergence. Our studies identify genetic pathways regulating CoV cross species transmission and receptor ortholog usage, resulting in robust animal models of human disease; critical reagents for therapeutic and vaccine testing.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology - A Study Section (VIRA)
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Stemmy, Erik J
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University of North Carolina Chapel Hill
Public Health & Prev Medicine
Schools of Public Health
Chapel Hill
United States
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Luo, Chu-Ming; Wang, Ning; Yang, Xing-Lou et al. (2018) Discovery of Novel Bat Coronaviruses in South China That Use the Same Receptor as Middle East Respiratory Syndrome Coronavirus. J Virol 92:
Gunaratne, Gihan S; Yang, Yang; Li, Fang et al. (2018) NAADP-dependent Ca2+ signaling regulates Middle East respiratory syndrome-coronavirus pseudovirus translocation through the endolysosomal system. Cell Calcium 75:30-41
Chefer, Svetlana; Seidel, Jurgen; Cockrell, Adam S et al. (2018) The Human Sodium Iodide Symporter as a Reporter Gene for Studying Middle East Respiratory Syndrome Coronavirus Pathogenesis. mSphere 3:
Zheng, Yuan; Shang, Jian; Yang, Yang et al. (2018) Lysosomal Proteases Are a Determinant of Coronavirus Tropism. J Virol 92:
Nakagawa, Keisuke; Narayanan, Krishna; Wada, Masami et al. (2018) The Endonucleolytic RNA Cleavage Function of nsp1 of Middle East Respiratory Syndrome Coronavirus Promotes the Production of Infectious Virus Particles in Specific Human Cell Lines. J Virol 92:
Zhao, Guangyu; He, Lei; Sun, Shihui et al. (2018) A Novel Nanobody Targeting Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Receptor-Binding Domain Has Potent Cross-Neutralizing Activity and Protective Efficacy against MERS-CoV. J Virol 92:
Douglas, Madeline G; Kocher, Jacob F; Scobey, Trevor et al. (2018) Adaptive evolution influences the infectious dose of MERS-CoV necessary to achieve severe respiratory disease. Virology 517:98-107
Du, Lanying; Yang, Yang; Zhou, Yusen et al. (2017) MERS-CoV spike protein: a key target for antivirals. Expert Opin Ther Targets 21:131-143
Peck, Kayla M; Scobey, Trevor; Swanstrom, Jesica et al. (2017) Permissivity of Dipeptidyl Peptidase 4 Orthologs to Middle East Respiratory Syndrome Coronavirus Is Governed by Glycosylation and Other Complex Determinants. J Virol 91:
Menachery, Vineet D; Graham, Rachel L; Baric, Ralph S (2017) Jumping species-a mechanism for coronavirus persistence and survival. Curr Opin Virol 23:1-7

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