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: 2019
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><Comorbidity><Coronaviridae><Coronavirus><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><General Viruses><Genes><Genetic Alteration><Genetic Change><Genetic defect><Human><Infection><Infection prevention><Lipids><Location><Lung infections><MERS-CoV><Measures><Mediating><Membrane Fusion><Mice><Mice Mammals><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome Coronavirus><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><Sequence-Specific Posttranscriptional Gene Silencing><Severe Acute Respiratory Syndrome><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-morbidity><coronavirus receptor><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><transmission process><vaccine development><vaccine formulation><vector><viral transmission><virology><virus protein><virus transmission>