Adaptive MERS coronavirus-cell entry pathways and their relevance to virulence and antiviral strategies

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Principal Investigator: Thomas Miller Gallagher
Organization: UNIVERSITY OF IOWA
Fiscal Year: 2021
Award: $266,291
Funding agency: National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY
The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a zoonotic virus
that can cause fatal disease in patients with underlying comorbidities. Further
recognition of this respiratory syndrome and prevention strategies will require a small
animal infection model as well as an additional understanding of the virus. This PPG
describes a mouse model of MERS-CoV disease. In this model, the viruses causing
disease are adapted variants, specialized for mouse lung infection. By contrast, non-
adapted MERS-CoVs cause infection in the mouse but do not cause disease. The
central hypothesis of this subproject (PPG2) is that mouse-adapted variants can
efficiently enter host cells through pathways that are not available to the non-adapted
viruses. To address this hypothesis, recombinant MERS-CoVs will be constructed and
evaluated to determine whether mouse-adaptive mutations in the cell entry-mediating
viral spike proteins correlate with efficient mouse lung infection. Surrogate MERS-CoV
pseudo-viruses will be constructed and evaluated to address the focused hypothesis that
mouse adapted variants mediate an “early” plasma-membrane cell entry that is
unavailable to non-adapted viruses. The project will dissect mechanisms by which spike
proteins mediate early cell entry through plasma membranes versus late cell entry
through endosomes. The basis for selection of early versus late cell entry will be
determined by identifying host cell factors promoting or restricting either pathway. This
project will also identify appropriate antiviral strategies that operate by preventing early
and late virus-cell entry. The rationale for all of these aims is that additional
understanding of MERS-CoV cell entry pathways will identify correlates of robust
infection and disease, and will also provide insights on the best ways to prevent infection
and disease with innovative virus entry inhibitors.

Terms: <Acute><Address><Adenoviridae><Adenoviruses><Adhesions><Affect><Animals><Antiproteases><Antiviral Agents><Antiviral Drugs><Antivirals><Automobile Driving><Binding><Camels><Cell Body><Cell Communication><Cell Culture Techniques><Cell Interaction><Cell membrane><Cell-to-Cell Interaction><Cells><Cleaved cell><CoV S protein><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><Coronaviridae><Coronavirus><Coronavirus glycoprotein S><Coronavirus spike protein><Cytoplasmic Membrane><Dipeptidyl Aminopeptidases><Dipeptidyl Peptidases><Dipeptidylpeptide Hydrolases><Disease><Disease Outbreaks><Disorder><Endopeptidase Inhibitors><Endosomes><Enzyme Gene><Enzymes><Epidemic><Esteroproteases><Evolution><Exhibits><Future><Genes><Genetic Alteration><Genetic Change><Genetic defect><Human><Infection><Infection prevention><Lipids><Location><Lung infections><MERS><MERS corona virus><MERS coronavirus><MERS coronavirus disease><MERS virus><MERS-CoV><MERS-CoV disease><Measures><Mediating><Membrane Fusion><Mice><Mice Mammals><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome coronavirus disease><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome-CoV><Modeling><Modern Man><Molecular Interaction><Mouse Protein><Murine><Mus><Mutation><Outbreaks><Pathogenesis><Pathway interactions><Patients><Peptidase Inhibitors><Peptidases><Peptide Hydrolase Inhibitors><Peptide Hydrolases><Peptide Peptidohydrolase Inhibitors><Peptides><Phenotype><Plasma Membrane><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Prevalence><Prevent infection><Preventative strategy><Prevention strategy><Preventive strategy><Procedures><Process><Protease Antagonists><Protease Gene><Protease Inhibitor><Proteases><Proteinase Inhibitors><Proteinases><Proteins><Proteolytic Enzymes><Quarantine><Quelling><RNA Interference><RNA Silencing><RNAi><Receptor Cell><Receptosomes><Recombinants><Research><Resistance><SARS><SARS Virus><SARS corona virus><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-Related Coronavirus><Sequence-Specific Posttranscriptional Gene Silencing><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Structure><Syndrome><Transmission><Variant><Variation><Viral><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virulence><Virus><Zoonoses><Zoonotic><Zoonotic Infection><adduct><anti-viral agents><anti-viral drugs><anti-virals><base><cell culture><cell type><cleaved><co-morbid><co-morbidity><comorbidity><corona virus><coronavirus S protein><coronavirus receptor><coronavirus spike glycoprotein><develop a vaccine><development of a vaccine><driving><genome mutation><human disease><human pathogen><improved><in vivo><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><insight><interest><isolation/quarantine><late endosome><mouse model><murine model><pathway><plasmalemma><pressure><prevent><preventing><pulmonary infections><resistant><respiratory><reverse genetics><severe acute respiratory syndrome-CoV><transmission process><vaccine development><vaccine formulation><vector><viral transmission><virology><virus protein><virus transmission>