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

doi:10.1073/pnas.0701849104

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

*Department of Virology, University of Freiburg, Hermann-Herder-Strasse 11, 79104 Freiburg, Germany; and
^†Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029

Communicated by Peter Palese, Mount Sinai School of Medicine, New York, NY, March 6, 2007 (received for review December 21, 2006)

Abstract

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.

Footnotes

^‡To whom correspondence may be addressed at:
Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, University of Freiburg, Hermann-Herder-Strasse 11, 79104 Freiburg, Germany.
E-mail: georg.kochs{at}uniklinik-freiburg.de or otto.haller{at}uniklinik-freiburg.de
Author contributions: P.S., A.G.-S., and G.K. designed research; D.G., P.S., M.H., I.K., L.M.-S., A.S., and G.K. performed research; O.H. contributed new reagents/analytic tools; D.G., P.S., M.H., I.K., A.G.-S., and G.K. analyzed data; and P.S., O.H., and G.K. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database [accession nos. EF190971–EF190978 (hvPR8 segments) and EF190979–EF190986(lvPR8 segments)].
Abbreviations:

CAT,

chloramphenicol acetyltransferase;

FLUAV,

influenza A virus;

hvPR8,

highly virulent influenza A/PR/8/34 virus;

NA,

neuraminidase;

NS1,

nonstructural protein-1;

MDCK,

Madin–Darby canine kidney.