title: Mapping of clinical and expression quantitative trait loci in a sex-dependent effect of host susceptibility to mouse-adapted influenza H3N2/HK/1/68.
abstract: Seasonal influenza outbreaks and recurrent influenza pandemics present major challenges to public health. By studying immunological responses to influenza in different host species, it may be possible to discover common mechanisms of susceptibility in response to various influenza strains. This could lead to novel therapeutic targets with wide clinical application. Using a mouse-adapted strain of influenza (A/HK/1/68-MA20 [H3N2]), we produced a mouse model of severe influenza that reproduces the hallmark high viral load and overexpression of cytokines associated with susceptibility to severe influenza in humans. We mapped genetic determinants of the host response using a panel of 29 closely related mouse strains (AcB/BcA panel of recombinant congenic strains) created from influenza-susceptible A/J and influenza-resistant C57BL/6J (B6) mice. Combined clinical quantitative trait loci (QTL) and lung expression QTL mapping identified candidate genes for two sex-specific QTL on chromosomes 2 and 17. The former includes the previously described Hc gene, a deficit of which is associated with the susceptibility phenotype in females. The latter includes the phospholipase gene Pla2g7 and Tnfrsf21, a member of the TNFR superfamily. Confirmation of the gene underlying the chromosome 17 QTL may reveal new strategies for influenza treatment.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec H3A 1B1, Canada.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Boivin
authors.forename: Julien
authors.initials: J
authors.lastname: Pothlichet
authors.forename: Emil
authors.initials: E
authors.lastname: Skamene
authors.forename: Earl G
authors.initials: EG
authors.lastname: Brown
authors.forename: J Concepción
authors.initials: JC
authors.lastname: Loredo-Osti
authors.forename: Robert
authors.initials: R
authors.lastname: Sladek
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Vidal
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000483:Alleles; D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D005838:Genotype; D058507:Host Specificity; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype; D007251:Influenza, Human / Q000235:genetics* / Q000276:immunology / Q000821:virology; D008168:Lung / Q000276:immunology / Q000821:virology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D010641:Phenotype; D054467:Phospholipases A2 / Q000235:genetics / Q000276:immunology; D040641:Quantitative Trait Loci; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology; D012737:Sex Factors
chemical_list: D018124:Receptors, Tumor Necrosis Factor; C485251:Tnfrsf21 protein, mouse; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C571209:Pla2g7 protein, mouse