University of North Carolina at Chapel Hill Graduate School
Doi
Abstract
Coronaviruses are a diverse family of viruses that infect a wide range of hosts, including both mammalian and avian species. Within recent history, coronaviruses have expanded their host range into humans, with four emergence events resulting in infections that cause only mild disease. However, two additional emergence events resulted in outbreaks of severe disease, causing heightened concern for public health. The 2003 severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in Southeast Asia and rapidly spread around the world with a 9 percent mortality rate before being controlled by public health intervention strategies. In 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) emerged from its zoonotic reservoir. To date, it has infected over 1800 people with a 36 percent mortality rate and is still circulating in the population. Due to the emergence of coronaviruses with pandemic potential, it is important to understand how these lineages have been able to expand their host range to infect new species. One key determinant of viral host range is the interaction between the virus spike protein and the host cell receptor. For MERS-CoV specifically, the virus can infect bats, camels (the putative intermediate host species), and humans, but is unable to infect mice or other traditional small animal models due to receptor incompatibilities. The inability of MERS-CoV to infect any small animal model species leaves us unable to study pathogenesis or begin to develop potential vaccines or therapeutics. Here, I present work on the biochemical determinants that govern MERS-CoV host range. Specifically, I 1) characterize the interactions between the MERS-CoV receptor binding domain and the mouse cell receptor; 2) investigate biochemical determinants that govern infection for other species; 3) attempt to generate a mouse-adapted MERS-CoV; and 4) present an approach to investigate potential evolutionary mechanisms of coronavirus host range expansion. This work has contributed to the development of a small animal model, allowing us to begin pathogenesis studies. Additionally, understanding the biochemical determinants and evolutionary mechanisms of coronavirus host range expansion can help evaluate the pandemic potential of currently circulating zoonotic strains and better prepare us for future pathogenic coronaviruses that may emerge.Doctor of Philosoph
