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Principal Investigator: Rebecca Michelle DuBois
Organization: UNIVERSITY OF CALIFORNIA SANTA CRUZ
Fiscal Year: 2019
Award: $363,921
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Human astroviruses (HAstV) are a leading cause of viral diarrhea in children. Divergent HAstV strains are
associated with fatal human encephalitis. Currently, no vaccines or antiviral therapies exist for HAstV
infections. Our goal is to identify sites of vulnerability (Achilles' heels) on the HAstV surface that can be
exploited for the development of preventative and therapeutic strategies against HAstV. The HAstV virion is a
small, icosahedral virus composed of an RNA genome surrounded by capsid protein. Despite the important
role of the HAstV capsid protein in virus entry into host cells, the location of antibody epitopes and the
mechanisms of virus-neutralizing antibodies are unknown. Our central hypothesis is that the HAstV capsid
spike domain plays a key role in virus entry and is a target of HAstV-neutralizing antibodies. Using a diverse
toolbox of structural, biochemical, immunological, and virological approaches, we will pursue three specific
aims to (1) use structural and biophysical studies to define HAstV capsid epitopes and serotype-reactivity of a
panel of six neutralizing monoclonal antibodies, (2) determine neutralizing mechanisms of a panel of
neutralizing monoclonal antibodies targeting the HAstV capsid spike, and define the role of the HAstV capsid
spike in cell entry, and (3) determine the structures of the divergent, neurotropic HAstV-VA1 capsid core and
spike, test their abilities to elicit neutralizing antibodies, and define HAstV-VA1 neutralizing epitopes. This work
represents the first molecular study of HAstV neutralizing epitopes. Results obtained by this work will elucidate
mechanisms of HAstV entry and neutralization and provide a foundation for the design of vaccines and
therapeutics to prevent and treat HAstV infections.
Terms: <0-11 years old><ATGN><Affinity><Amino Acids><Antibodies><Antibody titer measurement><Antigenic Determinants><Antigens><Antiviral Therapy><Assay><Astrovirus><Binding><Binding Determinants><Bioassay><Biochemical><Biologic Assays><Biological Assay><Biology><Blocking Antibodies><Brain Inflammation><Capsid><Capsid Proteins><Cell Attachment><Cell Body><Cell-Matrix Adhesions><Cell-Matrix Junction><Cells><Cellular Assay><Child><Child Youth><Childhood><Children (0-21)><Coat Proteins><Crystallization><Development><Diarrhea><Disease><Disorder><Elderly><Encephalitis><Endocytosis><Epitopes><Equipment><Foundations><General Viruses><Genome><Genotype><Goals><Health><Human><Immunize><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Individual><Infection><Knowledge><Location><Measures><Mice><Mice Mammals><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Murine><Mus><Non-Polyadenylated RNA><Patients><Peptide Domain><Play><Protein Domains><RNA><RNA Gene Products><Recombinant Antibody><Recombinants><Reporting><Research><Resolution><Ribonucleic Acid><Role><Rotavirus><Serotyping><Severity of illness><Site><Structure><Surface><Tertiary Protein Structure><Testing><Therapeutic><Therapeutic antibodies><VAC-TX><Vaccine Design><Vaccine Therapy><Vaccines><Viral><Viral Coat Proteins><Viral Genome><Viral Outer Coat Protein><Virion><Virus><Virus Particle><Virus-like particle><Work><adaptive immune response><advanced age><aminoacid><anti-viral therapy><antibody titering><biophysical analysis><biophysical studies><brain tissue><cell assay><children><childrens'><conformation><conformational state><design><designing><develop a vaccine><development of a vaccine><developmental><disease severity><elders><enteral pathogen><enteric pathogen><enteropathogen><experience><extracellular><geriatric><human tissue><immunogen><innovate><innovation><innovative><insight><intestinal pathogen><intestine pathogen><late life><later life><neurotropic><neutralizing antibody><neutralizing mAb><neutralizing monoclonal antibodies><new approaches><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel strategies><novel strategy><novel therapeutics><novel therapy><older adult><older person><pediatric><prevent><preventing><senior citizen><skills><social role><stool sample><stool specimen><therapeutic vaccination><vaccine development><vaccine formulation><viral infectious disease treatment><virology><virus genome><virus-like nanoparticles><viruslike particle><youngster>