The 21st century has recorded the emergence of three highly pathogenic respiratory coronaviruses, including Severe Acute Respiratory Coronavirus (SARS-CoV) in 2003, the ongoing Middle East Respiratory Coronavirus (MERS-CoV) in 2013 and a novel SARS-like coronaviruses SARS-CoV2 (SARS2) in Wuhan, China in Dec 2019. SARS2 causes COVID19, a severe acute respiratory distress syndrome (ARDS) and has infected 95000 individuals with ~20% severe cases and a ~3% mortality rate, resulting in over 3700 deaths. In the elderly, mortality rates approach 15%. The overall program goals are to identify the viral and host determinants, which regulate the atomic-level interactions between the SARS2 S-glycoprotein and various ACE2 receptor and associated entry components such as cellular proteases. The impact of these studies are high, as these interactions regulate 2019-nHCoV species specificity and host tropism, which play critical roles in viral pathogenesis and inform the evolutionary pathways leading to virus emergence and spread in humans and perhaps other intermediate hosts. In parallel, we apply these and other findings to developing robust mouse models of SARS2-mediated human disease, which is critical for not only evaluating viral pathogenesis but also for future testing of antiviral drugs, immunotherapeutics and vaccines.

Public Health Relevance

The proposal studies the mechanisms by which the SARS-like clade 1 SARS2 epidemic and zoonotic precursor strains use novel interaction networks to regulate cross species transmission and pathogenesis in mammals. The proposal develops novel reagents and animal models that support the global effort to control the spread and severity of COVID-19 disease.

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)
Program Officer
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:
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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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