Receptor recognition by viruses is the first and essential step of viral infections. It is an important determinant of viral host ranges and cross-species infections, and a primary target for human intervention. Coronaviruses recognize a variety of receptors, infect many hosts, and are significant health threats to humans and other animals. NL63 coronavirus (NL63-CoV), a prevalent human respiratory virus, is the only group-I coronavirus known to use angiotensin-converting enzyme 2 (ACE2) as its receptor, whereas other group-I coronaviruses use aminopeptidase-N (APN). Curiously, ACE2 is also used by group-II SARS coronavirus (SARS-CoV), the agent for the fatal human severe acute respiratory syndrome (SARS). Defined receptor-binding domains (RBDs) on the spike proteins of NL63-CoV and SARS-CoV bind ACE2 with high affinity. This research investigates the receptor recognition mechanisms and cross-species infections of coronaviruses. Our preliminary studies have determined the crystal structures of NL63-CoV RBD complexed with human ACE2 and of SARS-CoV RBD complexed with human ACE2. NL63-CoV and SARS-CoV RBDs have no structural homology in cores or receptor-binding motifs (RBMs) that directly contact ACE2, but recognize the same """"""""virus-binding hotspot"""""""" on ACE2. Among group-I coronaviruses, RBD cores are conserved, but RBMs are variable, explaining how these viruses recognize different receptors. We have also determined crystal structures of the RBDs from various SARS-CoV strains complexed with ACE2 proteins from humans and palm civets, revealing mechanisms whereby SARS-CoV transmitted between the two hosts. There are three specific aims in this project.
Aim 1 focuses on the receptor recognition mechanisms of group-I NL63-CoV. It investigates specific functions of the virus-binding hotspot on human ACE2 in NL63-CoV binding, and examines interactions between the NL63-CoV spike protein and ACE2 proteins from non-human hosts.
Aim 2 focuses on the receptor recognition mechanisms of other group-I coronaviruses. It investigates specific functions of the RBMs of other group-I coronavirus spike proteins, and studies whether modifying the RBMs changes the receptor specificities of the spike proteins.
Aim 3 focuses on the receptor recognition mechanisms of group-II SARS-CoV. It investigates why mutations in the RBM region of past SARS-CoV strains were selected, whether and how these mutations affect receptor binding, and what combinations of these mutations may appear in potential future SARS-CoV strains. The research approaches of this proposal include crystallographic analysis of the virus-receptor interfaces, identification of structural elements important for virus-receptor interactions, and characterization of these elements using crystallographic, biochemical, molecular, and virological tools. Overall, these studies will provide the molecular and structural basis for understanding viral evolution, virus-receptor interactions, viral host ranges and cross-species infections. They will also guide the development of novel antiviral strategies against coronavirus infections.
This research investigates how coronaviruses recognize their receptors and how they interact with receptors from different hosts. It explores novel principles governing viral evolution, virus-receptor interactions, viral host ranges and cross-species infections, and may lead to new approaches in the prevention and treatment of coronavirus infections in humans and other animals.
|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|
|Zheng, Yuan; Shang, Jian; Yang, Yang et al. (2018) Lysosomal Proteases Are a Determinant of Coronavirus Tropism. J Virol 92:|
|Shang, Jian; Zheng, Yuan; Yang, Yang et al. (2018) Cryo-Electron Microscopy Structure of Porcine Deltacoronavirus Spike Protein in the Prefusion State 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|
|Tai, Wanbo; Wang, Yufei; Fett, Craig A et al. (2017) Recombinant Receptor-Binding Domains of Multiple Middle East Respiratory Syndrome Coronaviruses (MERS-CoVs) Induce Cross-Neutralizing Antibodies against Divergent Human and Camel MERS-CoVs and Antibody Escape Mutants. J Virol 91:|
|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|
|Peng, Guiqing; Yang, Yang; Pasquarella, Joseph R et al. (2017) Structural and Molecular Evidence Suggesting Coronavirus-driven Evolution of Mouse Receptor. J Biol Chem 292:2174-2181|
|Hou, Yixuan; Lin, Chun-Ming; Yokoyama, Masaru et al. (2017) Deletion of a 197-Amino-Acid Region in the N-Terminal Domain of Spike Protein Attenuates Porcine Epidemic Diarrhea Virus in Piglets. J Virol 91:|
Showing the most recent 10 out of 32 publications