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Principal Investigator: Shinji Makino
Organization: UNIVERSITY OF TEXAS MED BR GALVESTON
Fiscal Year: 2021
Award: $197,500
Funding agency: National Institute of Allergy and Infectious Diseases
Rift Valley fever Phlebovirus (RVFV), a bunyavirus, belongs to the NIAID Category A list of pathogens and the CDC list of potential bioterrorism agents. RVFV causes a disease that is endemic in sub-Saharan Africa and can emerge in explosive, mosquito-borne epidemics that decimate herds of sheep and cattle, resulting in enormous economic losses. In humans, RVFV infection may cause hemorrhagic fever, encephalitis, and retinal vasculitis. Many different mosquitoes, including several species native to North America, are competent vectors for RVFV transmission. The introduction of RVFV into North America would likely cause panic in the general population, and the effects on livestock could have a devastating economic impact. The lack of availability of licensed vaccines or anti-RVFV reagents for use in humans or domestic animals is of great concern. RVFV carries a tripartite, single-stranded, negative-sense RNA genome, including L RNA encoding L protein, M RNA encoding two major envelope glycoproteins, Gn and Gc, and S RNA encoding N and NSs. NSs is the major virulence factor that efficiently suppresses host antiviral responses. The S RNA uses an ambi-sense strategy for gene expression; NSs is translated from the mRNA that is transcribed from the antigenomic-sense S RNA, whereas N protein is produced from the mRNA that is transcribed from the genomic-sense S RNA. One of the essential steps in virus replication and dissemination is the packaging of viral genome into virus particles, however, the mechanisms of viral RNA packaging in RVFV and other bunyaviruses are largely unknown. Insight into the underlying rules and mechanisms that govern the packaging of viral RNA genome into RVFV particles is valuable for understanding the regulation of virus replication, virus evolution, and the pathogenesis of the virus. This knowledge is also critical for the development of antiviral drugs that can inhibit infectious virus production or for the development of a live- attenuated vaccine strain. We propose that a direct interaction of Gn with the viral RNA segments is the primary factor that influences the packaging efficiencies of viral RNAs into RVFV particles. The present application will clarify the mechanism and biological significance of efficient packaging of antigenomic S RNA into virus particles by characterizing the direct interaction of Gn with antigenomic S RNA, identify the Gn- binding sites in viral RNAs, and examine the importance of antigenomic S RNA packaging for RVFV replication. The data obtained from the proposed studies will clarify the fundamental mechanisms that drive viral RNA packaging in RVFV and other bunyaviruses, with the overall goal of informing the design of novel antivirals and vaccines.
Terms: <Africa><Africa South of the Sahara><Agriculture><Animals><Anti-Viral Response><Antiviral Agents><Antiviral Drugs><Antiviral Response><Antivirals><Assay><Attenuated Vaccines><Binding Sites><Bioassay><Biologic Assays><Biological><Biological Assay><Biological Terrorism><Bioterrorism><Bovine Species><Brain Inflammation><Bunyavirus><CDC><Categories><Cattle><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Centers for Disease Control><Centers for Disease Control and Prevention><Centers for Disease Control and Prevention (U.S.)><Code><Coding System><Combining Site><Country><Culicidae><Cytoplasm><Cytoplasmic Domain><Cytoplasmic Tail><Data><Development><Diminished Vision><Disease><Disease Outbreaks><Disorder><Domestic Animals><EC 2.7.7.48><Economics><Elements><Encephalitis><Endemic Diseases><Epidemic><Evolution><Farm Animal><Gene Expression><General Population><General Public><Genome><Genomics><Genus Phlebovirus><Glycoproteins><Goals><Golgi><Golgi Apparatus><Golgi Complex><Human><IFN><Immune response><Immunological response><Infection><Innate Immune Response><Interferons><Intracellular Communication and Signaling><Knowledge><Life Cycle><Life Cycle Stages><Live-attenuated Vaccine><Livestock><Low Vision><Mediating><Messenger RNA><Modern Man><Mosquitoes><Movement><NIAID><National Institute of Allergy and Infectious Disease><Non-Polyadenylated RNA><Non-structural Protein><Nonstructural Protein><North America><Nucleocapsid Proteins><Orthobunyavirus><Outbreaks><Ovine><Ovis><Panic><Partial Sight><Pathogenicity Factors><Patients><Phlebovirus><Population><Production><Proteins><Public Health><RNA><RNA Gene Products><RNA Replicase><RNA Viruses><RNA chemical synthesis><RNA synthesis><RNA-Dependent RNA Polymerase><RNA-Directed RNA Polymerase><Reactive Site><Reagent><Reduced Vision><Regulation><Research><Retina><Retinal Vasculitis><Ribonucleic Acid><Ribonucleoproteins><Rift Valley Fever><Role><Ruminantia><Ruminants><Sheep><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Sub-Saharan Africa><Subnormal Vision><Subsaharan Africa><System><Testing><Translating><Transmission><United States Centers for Disease Control><United States Centers for Disease Control and Prevention><Vaccines><Viral><Viral Genome><Viral Hemorrhagic Fevers><Viral Packaging><Viral Pathogenesis><Virion><Virulence Factors><Virus><Virus Assembly><Virus Packagings><Virus Particle><Virus Replication><Visual impairment><agricultural><anti-viral agents><anti-viral drugs><anti-virals><biological signal transduction><body movement><bovid><bovine><cow><design><designing><developmental><domesticated animal><economic impact><genomic RNA><hemorrhagic fever><host response><immune system response><immunoresponse><insight><life course><live vaccine><live vaccines><mRNA><macula><macular><mosquito-borne><mosquitoborne><mutant><novel><particle><pathogen><programs><sandfly fever virus group><social role><transmission process><vector><viral RNA><viral assembly><viral genomics><viral multiplication><viral replication><virus RNA><virus genome><virus genomics><virus multiplication><virus pathogenesis><vision impairment><visually impaired>