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The role of the N-terminal caspase cleavage site in the nucleoprotein of influenza A virus in vitro and in vivo. 2008

A S Lipatov, and H-L Yen, and R Salomon, and H Ozaki, and E Hoffmann, and R G Webster
Division of Virology, Department of Infectious Diseases, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA.

The N-terminal caspase cleavage in the nucleoprotein (NP) of influenza A virus is correlated with the host origin of the virus, thus could be a molecular determinant for host range. We studied how mutations targeting the NP cleavage motif of human and avian influenza viruses affect virus replication in vitro and in vivo. The "avian-like" D16-->G substitution in the NP, which makes this protein resistant to cleavage, did not significantly affect the human A/Puerto Rico/8/34 (H1N1) virus replication in vitro but decreased the lethality of this virus in mice by 68-fold. Gene incompatibility contributed to the attenuated phenotype of the reassortant A/Puerto Rico/8/34 virus with avian NP derived from A/Teal/Hong Kong/w312/97 (H6N1) virus in vitro and in vivo. Insertion of the "human-like" G16-->D mutation into avian NP, which resulted in susceptibility to caspase cleavage, did not rescue virulence, but made the reassortant virus even more attenuated. Introducing the human-like G16-->D substitution into the NP of highly pathogenic A/Vietnam/1203/04 (H5N1) virus decreased lethality in mice. We confirmed that position 16, which associated with the N-terminal caspase cleavage of the NP, is important for optimal virus fitness in vitro and in vivo. An avian-like mutation at position 16 in the NP of human virus as well as a human-like substitution at this residue in avian NP both resulted in virus attenuation.

UI MeSH Term Description Entries
D007251 Influenza, Human An acute viral infection in humans involving the respiratory tract. It is marked by inflammation of the NASAL MUCOSA; the PHARYNX; and conjunctiva, and by headache and severe, often generalized, myalgia. Grippe,Human Flu,Human Influenza,Influenza in Humans,Influenza,Flu, Human,Human Influenzas,Influenza in Human,Influenzas,Influenzas, Human
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D009698 Nucleoproteins Proteins conjugated with nucleic acids. Nucleoprotein
D009980 Influenza A virus The type species of the genus ALPHAINFLUENZAVIRUS that causes influenza and other diseases in humans and animals. Antigenic variation occurs frequently between strains, allowing classification into subtypes and variants. Transmission is usually by aerosol (human and most non-aquatic hosts) or waterborne (ducks). Infected birds shed the virus in their saliva, nasal secretions, and feces. Alphainfluenzavirus influenzae,Avian Orthomyxovirus Type A,FLUAV,Fowl Plague Virus,Human Influenza A Virus,Influenza Virus Type A,Influenza Viruses Type A,Myxovirus influenzae-A hominis,Myxovirus influenzae-A suis,Myxovirus pestis galli,Orthomyxovirus Type A,Orthomyxovirus Type A, Avian,Orthomyxovirus Type A, Human,Orthomyxovirus Type A, Porcine,Pestis galli Myxovirus,Fowl Plague Viruses,Influenza A viruses,Myxovirus influenzae A hominis,Myxovirus influenzae A suis,Myxovirus, Pestis galli,Myxoviruses, Pestis galli,Pestis galli Myxoviruses,Plague Virus, Fowl,Virus, Fowl Plague
D011995 Recombination, Genetic Production of new arrangements of DNA by various mechanisms such as assortment and segregation, CROSSING OVER; GENE CONVERSION; GENETIC TRANSFORMATION; GENETIC CONJUGATION; GENETIC TRANSDUCTION; or mixed infection of viruses. Genetic Recombination,Recombination,Genetic Recombinations,Recombinations,Recombinations, Genetic
D002645 Chickens Common name for the species Gallus gallus, the domestic fowl, in the family Phasianidae, order GALLIFORMES. It is descended from the red jungle fowl of SOUTHEAST ASIA. Gallus gallus,Gallus domesticus,Gallus gallus domesticus,Chicken
D005585 Influenza in Birds Infection of domestic and wild fowl and other BIRDS with INFLUENZA A VIRUS. Avian influenza usually does not sicken birds, but can be highly pathogenic and fatal in domestic POULTRY. Avian Flu,Avian Influenza,Fowl Plague,Influenza, Avian,Avian Influenzas,Flu, Avian,Influenza in Bird,Influenzas, Avian,Plague, Fowl
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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