Abstract
The mouse is the most widely used animal model for influenza virus research. However, the susceptibility of mice to seasonal influenza virus depends on the strain of mouse and on the strain of the influenza virus. Seasonal A/H3N2 influenza viruses do not replicate well in mice and therefore they need to be adapted to this animal model. In this study, we generated a mouse-adapted A/H3N2 virus (A/Switzerland/9715293/2013 [MA-H3N2]) by serial passaging in mouse lungs that exhibited greater virulence compared to the wild-type virus (P0-H3N2). Seven mutations were found in the genome of MA-H3N2: PA(K615E), NP(G384R), NA(G320E) and HA(N122D, N144E, N246K, and A304T). Using reverse genetics, two synergistically acting genes were found as determinants of the pathogenicity in mice. First, the HA substitutions were shown to enhanced viral replication in vitro and, second, the PA-K615E substitution increased polymerase activity, although did not alter virus replication in vitro or in mice. Notably, single mutations had only limited effects on virulence in vitro. In conclusion, a co-contribution of HA and PA mutations resulted in a lethal mouse model of seasonal A/H3N2 virus. Such adapted virus is an excellent tool for evaluation of novel drugs or vaccines and for study of influenza pathogenesis.
Highlights
The mouse is the most widely used animal model for influenza virus research
The hemagglutinin (HA), neuraminidase (NA) and matrix 2 (M2) proteins are embedded in the viral envelope, whereas viral polymerase proteins (PB1, PB2, and PA), nucleoprotein (NP), matrix 1 (M1), non-structural protein 1 (NS1) and nuclear export protein (NEP) are localized inside the virion
A group of three mice were given a dose of cyclophosphamide (100 mg/kg) one day before intranasal infection with 2.5 × 105 plaque-forming units (PFU)/50 μl of the parental A/H3N2 virus (P0-H3N2)
Summary
The mouse is the most widely used animal model for influenza virus research. the susceptibility of mice to seasonal influenza virus depends on the strain of mouse and on the strain of the influenza virus. Seasonal A/H3N2 influenza viruses do not replicate well in mice and they need to be adapted to this animal model. A cocontribution of HA and PA mutations resulted in a lethal mouse model of seasonal A/H3N2 virus Such adapted virus is an excellent tool for evaluation of novel drugs or vaccines and for study of influenza pathogenesis. The susceptibility of mice to influenza viruses depends on both mouse and viral strains. Mice are not naturally infected with seasonal influenza viruses and infections are typically asymptomatic with little or no viral replication. The basis of this phenomenon is that inbred mice possess an interferon-inducible restriction factor known as Mx13. We report on a novel combination of substitutions in HA (N122D, N144E, N246K and A304T) and PA (K615E) proteins responsible for the adaptation and increased pathogenicity of a contemporary A/H3N2 seasonal virus in mice
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