Replication fitness determines high virulence of influenza A virus in mice carrying functional Mx1 resistance gene

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 16; pp. 6806 - 6811
• Main Authors: Grimm, Daniel, Staeheli, Peter, Hufbauer, Martin, Koerner, Iris, Martínez-Sobrido, Luis, Solórzano, Alicia, García-Sastre, Adolfo, Haller, Otto, Kochs, Georg
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17.04.2007; National Acad Sciences
• Subjects: Animals; Antivirals; Biological Sciences; Cell Line; Dogs; Gene expression; Genes; GTP-Binding Proteins - biosynthesis; GTP-Binding Proteins - deficiency; GTP-Binding Proteins - genetics; GTP-Binding Proteins - physiology; Immune system; Infections; Influenza; Influenza A virus; Influenza A Virus, H1N1 Subtype - genetics; Influenza A Virus, H1N1 Subtype - growth & development; Influenza A Virus, H1N1 Subtype - pathogenicity; Lethal dose 50; Lungs; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Myxovirus Resistance Proteins; Orthomyxoviridae Infections - genetics; Orthomyxoviridae Infections - virology; Plasmids; RNA; Rodents; Vero cells; Virology; Virulence; Virulence - genetics; Virus Replication - genetics; Virus Replication - physiology; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0701849104

The IFN-induced resistance factor Mx1 is a critical component of innate immunity against influenza A viruses (FLUAV) in mice. Animals carrying a wild-type Mx1 gene (Mx1⁺/⁺) differ from regular laboratory mice (Mx1⁻/⁻) in that they are highly resistant to infection with standard FLUAV strains. We identified an extraordinary variant of the FLUAV strain, A/PR/8/34 (H1N1) (designated hvPR8), which is unusually virulent in Mx1⁺/⁺ mice. hvPR8 was well controlled in Mx1⁺/⁺ but not Mx1⁻/⁻ mice provided that the animals were treated with IFN before infection, indicating that hvPR8 exhibits normal sensitivity to growth restriction by Mx1. hvPR8 multiplied much faster than standard PR8 early in infection because of highly efficient viral gene expression in infected cells. Studies with reassortant viruses containing defined genome segments of both hvPR8 and standard PR8 demonstrated that the HA, neuraminidase, and polymerase genes of hvPR8 all contributed to virulence, indicating that efficient host cell entry and early gene expression renders hvPR8 highly pathogenic. These results reveal a surprisingly simple concept of how influenza viruses may gain virulence and illustrate that high speed of virus growth can outcompete the antiviral response of the infected host.