title: Host genetic variation affects resistance to infection with a highly pathogenic H5N1 influenza A virus in mice.
abstract: Despite the prevalence of H5N1 influenza viruses in global avian populations, comparatively few cases have been diagnosed in humans. Although viral factors almost certainly play a role in limiting human infection and disease, host genetics most likely contribute substantially. To model host factors in the context of influenza virus infection, we determined the lethal dose of a highly pathogenic H5N1 virus (A/Hong Kong/213/03) in C57BL/6J and DBA/2J mice and identified genetic elements associated with survival after infection. The lethal dose in these hosts varied by 4 logs and was associated with differences in replication kinetics and increased production of proinflammatory cytokines CCL2 and tumor necrosis factor alpha in susceptible DBA/2J mice. Gene mapping with recombinant inbred BXD strains revealed five loci or Qivr (quantitative trait loci for influenza virus resistance) located on chromosomes 2, 7, 11, 15, and 17 associated with resistance to H5N1 virus. In conjunction with gene expression profiling, we identified a number of candidate susceptibility genes. One of the validated genes, the hemolytic complement gene, affected virus titer 7 days after infection. We conclude that H5N1 influenza virus-induced pathology is affected by a complex and multigenic host component.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Adrianus C M
authors.initials: AC
authors.lastname: Boon
authors.forename: Jennifer
authors.initials: J
authors.lastname: deBeauchamp
authors.forename: Anna
authors.initials: A
authors.lastname: Hollmann
authors.forename: Jennifer
authors.initials: J
authors.lastname: Luke
authors.forename: Malak
authors.initials: M
authors.lastname: Kotb
authors.forename: Sarah
authors.initials: S
authors.lastname: Rowe
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Webby
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D020869:Gene Expression Profiling; D014644:Genetic Variation; D054884:Host-Pathogen Interactions; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics / Q000472:pathogenicity*; D007251:Influenza, Human / Q000401:mortality / Q000821:virology; D051379:Mice / Q000821:virology; D008810:Mice, Inbred C57BL / Q000235:genetics / Q000821:virology*; D008811:Mice, Inbred DBA / Q000235:genetics / Q000821:virology*; D008817:Mice, Mutant Strains; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000401:mortality* / Q000821:virology; D040641:Quantitative Trait Loci; D011995:Recombination, Genetic; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D014409:Tumor Necrosis Factor-alpha
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