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Principal Investigator: Fang Li
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2019
Award: $455,796
Funding agency: National Institute of Allergy and Infectious Diseases
Receptor recognition and cell entry by viruses are two initial and essential steps in viral infection cycles. They are important determinants of viral host ranges, tissue tropisms and pathogenesis, and are primary targets for human intervention. Coronaviruses (CoVs) pose serious health threats to humans and other animals. SARS-CoV and MERS-CoV have infected thousands of people with significant fatality, whereas porcine epidemic diarrhea CoV is currently causing ~100% fatality in piglets. A virus-surface spike protein guides CoV entry into host cells by binding to its host receptor via its S1 subunit and fusing viral and host membranes via its S2 subunit. S1 from different CoVs recognizes a variety of host receptors through one or both of its domains (S1-NTD and S1-CTD), and the S1/S2 boundary is cleaved by host proteases for activation of membrane fusion by S2. Our previous research has determined a number of crystal structures of CoV S1 domains by themselves or in complex with their respective receptor, and also shown how proteolysis regulates the cell entry of some CoVs. Our research has contributed critically to the current knowledge about the molecular mechanisms for CoV receptor recognition, cell entry, and cross-species transmission. In this competitive renewal of R01, we will continue to investigate how CoVs exploit host receptors and host proteases for cell entry. This proposal has three specific aims. Aim 1 examines receptor binding by CoV S1-NTDs. Specifically, we will investigate whether S1-NTDs from different CoV genera have the same structural fold and evolutionary origin as host galectins (galactose-binding lectins). We will also examine how CoV S1-NTDs recognize sugar receptors. These studies will reveal the evolutionary origins of CoV S1-NTDs, enhance understanding of sugar recognition by CoVs, and may facilitate future design of sugar analogues and subunit vaccines to inhibit CoV infections. Aim 2 focuses on receptor binding by CoV S1-CTDs. Specifically, we will analyze the interactions between the S1-CTDs of bat SARS-like CoVs (SL-CoVs) and the protein receptor homologues from humans and other animals, and elucidate how bat SL-CoVs transmitted to humans and other animals to cause the SARS epidemic through evolutionary changes in their S1-CTDs. These studies will provide critical information for understanding emergence potential of bat SL-CoVs and for facilitating epidemic monitoring and control. Aim 3 investigates cell entry by CoVs. Specifically, we will investigate what host proteases activate CoV entry and how the proteases motifs in CoV spikes have evolved to modulate CoV entry. These studies will reveal how host proteases regulate CoV entry to meet their specific need for host range, tissue tropism and pathogenesis, and may facilitate future design of protease inhibitors to block CoV entry. Overall, this proposal investigates the molecular and structural mechanisms for receptor recognition, cell entry, cross-species transmission, and tissue tropism of CoVs, which will lead to novel principles in virology. This research is also important for evaluating the emerging disease potentials of CoVs and for preventing, controlling and treating CoV infections in humans and other animals.
Terms: <Animals><Antiproteases><Antiviral Agents><Antiviral Drugs><Antivirals><Assay><Attenuated><Bats><Binding><Bioassay><Biochemical><Biologic Assays><Biologic Models><Biological Assay><Biological Models><Bovine Species><CD66a antigen><CEACAM1><Cattle><Cell Body><Cells><Chiroptera><Civet Cats><Civets><Cleaved cell><Complex><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Coronavirus spike protein><Crystallization><D-Galactoside-Binding Lectin><Development><Diarrhea><Disease><Disease Outbreaks><Disorder><Electrons><Endopeptidase Inhibitors><Epidemic><Esteroproteases><Evolution><Family><Family suidae><Funding><Future><Galactose Binding Lectin><Galaptins><Galectins><GeneHomolog><General Viruses><Genetic Alteration><Genetic Change><Genetic defect><Goals><Grant><Health><Homolog><Homologous Gene><Homologue><Human><Infection><Intervention><Intervention Strategies><Intestinal><Intestines><Knowledge><Macromolecular Structure><Mammalia><Mammals><Membrane><Membrane Fusion><Mice><Mice Mammals><Microscopic><Model System><Modeling><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Molecular Structure><Monitor><Murine><Mus><Mutation><Negative Beta Particle><Negatrons><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Outbreaks><Pathogenesis><Pathway interactions><Peptidase Inhibitors><Peptidases><Peptide Hydrolase Inhibitors><Peptide Hydrolases><Peptide Peptidohydrolase Inhibitors><Pigs><Play><Protease Antagonists><Protease Gene><Protease Inhibitor><Proteases><Protein Cleavage><Proteinase Inhibitors><Proteinases><Proteins><Proteolysis><Proteolytic Enzymes><Receptor Protein><Research><Role><S-Type Lectins><SARS><SARS Virus><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-Related Coronavirus><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome Virus><Structure><Subunit Vaccines><Suidae><Surface><Swine><Testing><Transmission><Tropism><Urbani SARS-Associated Coronavirus><Viral><Viral Diseases><Virus><Virus Diseases><Viverridae><analog><anti-viral agents><anti-viral drugs><anti-virals><beta-D-Galactosyl-Specific Lectin><beta-Galactoside Binding Lectin><bovid><bovine><bowel><cleaved><conformation><conformational state><coronavirus receptor><cow><design><designing><developmental><extracellular><genome mutation><inhibitor><inhibitor/antagonist><interdisciplinary approach><interventional strategy><membrane structure><multidisciplinary approach><neuronal><neurotropic><novel><pathway><porcine><prevent><preventing><receptor><receptor binding><receptor bound><receptor expression><reverse genetics><social role><sugar><suid><tissue tropism><transmission process><viral infection><virology><virus infection><virus-induced disease>