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Principal Investigator: Jianrong Li
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2019
Award: $498,053
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
This application is to renew a grant to study RNA methylation in pneumoviruses. Pneumoviridae is a new virus
family, created in 2016 by elevating the paramyxoviral subfamily Pneumovirinae to family status. The
Pneumoviridae family includes two medically important pathogens, human respiratory syncytial virus (RSV) and
human metapneumovirus (hMPV), which are the leading causative agents of acute viral respiratory tract
infections in infants, young children, the elderly, and immunocompromised individuals. Despite the enormous
economic loss and emotional burden these viruses cause, no vaccines or anti-viral drugs are currently available.
Development of such agents requires a better understanding of all aspects of their life cycle. In the last grant
period, we have revealed the unique mechanism of mRNA capping and cap methylation in pneumoviruses. We
recently discovered that pneumovirus genome, antigenome, and mRNAs are also methylated at internal
adenosine residues to form N6-methyladenosine (m6A) by host m6A methyltransferase complex. Although m6A
methylation has been discovered in viral RNA in early 1970s, the biological function of m6A in the virus life cycle,
pathogenesis, and immunity has been a mystery for four decades. We have found that the internal m6A
methylation in viral RNAs promotes pneumovirus replication and gene expression. The objectives of the current
application are to determine the roles of internal m6A methylation in pneumovirus replication and pathogenesis
in vivo; and to define mechanism(s) by which m6A methylation modulate pneumovirus life cycle. Our Specific
Aims are: (1) to define the host m6A machinery that regulates pneumovirus replication and gene expression; (2)
to define the mechanism(s) by which internal m6A promote pneumovirus replication and gene expression; and
(3) to define the roles of m6A methylation in pneumovirus replication and pathogenesis in a cotton rat model. The
successful completion of this work will not only advance our understanding of m6A methylation in regulating
pneumovirus life cycle and pathogenesis, but also provide a novel approach for developing live attenuated
vaccine candidates and antiviral drugs by inhibiting viral m6A methylation.
Terms: <0-11 years old><5' Capped RNA><5' mRNA Cap Structure><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Adenosine><Animal Model><Animal Models and Related Studies><Antiviral Agents><Antiviral Drugs><Antivirals><Attenuated Live Virus Vaccine><Binding><Biochemical Genetics><Biological Function><Biological Process><Cell Body><Cells><Child><Child Youth><Children (0-21)><Complex><Cotton Rats><Development><EC 2.1.1><Economics><Elderly><Emotional><Enzyme Gene><Enzymes><Epithelial><Epithelial Cells><Eukaryota><Eukaryote><FDA approved><Family><Gene Expression><General Viruses><Genetic Alteration><Genetic Change><Genetic Translation><Genetic defect><Genome><Grant><HCV><HIV><HeLa><Hela Cells><Hepatitis C virus><Human><Human Immunodeficiency Viruses><Human Metapneumovirus><Immunity><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><Individual><Infant><Influenza Virus><Intermediary Metabolism><Knock-out><Knockout><LAV-HTLV-III><Life Cycle><Life Cycle Stages><Live-attenuated Vaccine><Lymphadenopathy-Associated Virus><Mediating><Medical><Messenger RNA><Metabolic Processes><Metabolism><Methylation><Methyltransferase><Modeling><Modern Man><Modification><Molecular Interaction><Mononegavirales><Mutation><Non-Polyadenylated RNA><Nucleocapsid Proteins><Pathogenesis><Pneumovirinae><Pneumovirus><Proteins><RNA><RNA Caps><RNA Gene Products><RNA Stability><RNA methylation><Reader><Recombinants><Research><Respiratory syncytial virus><Ribonucleic Acid><Ribonucleoproteins><Role><Series><Site><System><Testing><Translations><VSV><Vaccines><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Viral><Viral Genes><Viral Genome><Viral Pathogenesis><Viral Respiratory Tract Infection><Virulence><Virus><Virus Replication><Virus-HIV><Work><advanced age><anti-viral agents><anti-viral drugs><anti-virals><attenuation><children><childrens'><design><designing><developmental><elders><genetic approach><genetic information><genome mutation><geriatric><immunosuppressed patient><in vivo><influenzavirus><knock-down><knockdown><late life><later life><life course><mRNA><mRNA Translation><mRNA capping><methylase><model of animal><model organism><new approaches><new vaccines><next generation vaccines><novel><novel approaches><novel strategies><novel strategy><novel vaccines><older adult><older person><overexpress><overexpression><pathogen><public health relevance><recombinant virus><reverse genetics><senior citizen><social role><transmethylase><vaccine candidate><viral RNA><viral multiplication><viral replication><viral respiratory infection><virus RNA><virus genome><virus multiplication><virus pathogenesis><youngster>