Mapping of Clinical and Expression Quantitative Trait Loci in a Sex-Dependent Effect of Host Susceptibility to Mouse-Adapted Influenza H3N2/HK/1/68
Open Access
- 15 April 2012
- journal article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 188 (8), 3949-3960
- https://doi.org/10.4049/jimmunol.1103320
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.Keywords
This publication has 70 references indexed in Scilit:
- Antibody responses and cross protection against lethal influenza A viruses differ between the sexes in C57BL/6 miceVaccine, 2011
- Noninvasive molecular imaging reveals role of PAF in leukocyte‐endothelial interaction in LPS‐induced ocular vascular injuryThe FASEB Journal, 2011
- Gender differences in expression of the human caspase-12 long variant determines susceptibility to Listeria monocytogenes infectionProceedings of the National Academy of Sciences of the United States of America, 2009
- Enhanced Innate Immune Responsiveness to PulmonaryCryptococcus neoformansInfection Is Associated with Resistance to Progressive InfectionInfection and Immunity, 2008
- Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque developmentNature Medicine, 2008
- IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis virusesProceedings of the National Academy of Sciences of the United States of America, 2007
- Herpes Simplex Virus Encephalitis in Human UNC-93B DeficiencyScience, 2006
- Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virusNature, 2006
- The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9Nature Immunology, 2006
- Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell–mediated innate resistance to cytomegalovirus infectionNature Genetics, 2005