The long-term goal of this project is to understand the virus-host interactions that are critical to the disease caused by the coronavirus associated with Severe Acute Respiratory Syndrome in humans (SARS-CoV). This understanding is required to develop potential treatments, and inhibitors of the disease that is caused by this emerging pathogen. It is believed that the outbreak of Severe Acute Respiratory Syndrome began in the Guangdong Province of China in November, 2002. Since its emergence, SARS-CoV has infected thousands of people throughout the globe. SARS-CoV is a novel coronavirus that is readily isolated from the lungs, throat swabs, and feces specimens of infected people. Serological studies indicate that SARS-CoV had not infected humans in the USA or Hong Kong prior to the current outbreak, illustrating that it is a new human pathogen. The SARS-CoV outbreak in people is extraordinary because of the high morbidity and mortality associated with infection. It is clear that animal models of the disease caused by SARS-CoV are required to combat this emerging pathogen, which has both epidemic and pandemic potential. To our knowledge SARS-CoV has been inoculated into mice, pigs, chickens, and primates. To date, only monkeys have been infected by the virus. The limitation of infection to only very closely related species, such as humans and monkeys, is not surprising, because the interaction between the coronavirus attachment protein and the host cell receptor is very precise. Virus-receptor interactions are responsible for the species specificity and pathogenesis of many different coronaviruses that infect people, pigs, cats, dogs, and mice. Although monkeys, and potentially other animals, will be important to study the virus, a mouse model for SARS-CoV is crucial for the evaluation of antiviral treatments, vaccine strategies, and studies of pathogenesis. However, data suggests that normal mice are not permissive to infection by SARS-CoV. Our objective is to develop a small animal model for SARS-CoV by creating transgenic mice that express the receptor(s) utilized by the virus. To accomplish this goal; we will create transgenic mice that express the receptor(s) for SARS-CoV, examine the susceptibility of these transgenic mice to SARS-CoV, and analyze the prevention or treatment of SARS-CoV infection in the transgenic mice. Addressing these aims will produce an excellent small animal model of SARS-CoV infection in people, as well as, expand our understandin 9 of processes important in pathogenesis, and the emer0ence of new viruses in humans.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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University of Colorado Denver
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Zhou, Bin; Pearce, Melissa B; Li, Yan et al. (2013) Asparagine substitution at PB2 residue 701 enhances the replication, pathogenicity, and transmission of the 2009 pandemic H1N1 influenza A virus. PLoS One 8:e67616
Zhou, Bin; Wentworth, David E (2012) Influenza A virus molecular virology techniques. Methods Mol Biol 865:175-92
Funk, C Joel; Wang, Jieru; Ito, Yoko et al. (2012) Infection of human alveolar macrophages by human coronavirus strain 229E. J Gen Virol 93:494-503
Chen, Lanfen; Chen, Zhangguo; Baker, Kristi et al. (2012) The short isoform of the CEACAM1 receptor in intestinal T cells regulates mucosal immunity and homeostasis via Tfh cell induction. Immunity 37:930-46
Zhou, Bin; Li, Yan; Speer, Scott D et al. (2012) Engineering temperature sensitive live attenuated influenza vaccines from emerging viruses. Vaccine 30:3691-702
Zhou, Bin; Jerzak, Greta; Scholes, Derek T et al. (2011) Reverse genetics plasmid for cloning unstable influenza A virus gene segments. J Virol Methods 173:378-83
Zhou, Bin; Li, Yan; Halpin, Rebecca et al. (2011) PB2 residue 158 is a pathogenic determinant of pandemic H1N1 and H5 influenza a viruses in mice. J Virol 85:357-65
Peng, Guiqing; Sun, Dawei; Rajashankar, Kanagalaghatta R et al. (2011) Crystal structure of mouse coronavirus receptor-binding domain complexed with its murine receptor. Proc Natl Acad Sci U S A 108:10696-701
Osborne, Christina; Cryan, Paul M; O'Shea, Thomas J et al. (2011) Alphacoronaviruses in New World bats: prevalence, persistence, phylogeny, and potential for interaction with humans. PLoS One 6:e19156
Zhou, Bin; Li, Yan; Belser, Jessica A et al. (2010) NS-based live attenuated H1N1 pandemic vaccines protect mice and ferrets. Vaccine 28:8015-25

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