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Proc Natl Acad Sci U S A. 2017 Mar 28;114(13):3491-3496. doi: 10.1073/pnas.1620889114. Epub 2017 Feb 27.

Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection.

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Department of Medicine, University of Vermont, Burlington, VT 05405.
Department of Surgery, University of Vermont, Burlington, VT 05405.
Department of Medical Biostatistics, University of Vermont, Burlington, VT 05405.
Department of Medicine, University of Vermont, Burlington, VT 05405;
Department of Pathology, University of Vermont, Burlington, VT 05405.


Males of many species, ranging from humans to insects, are more susceptible than females to parasitic, fungal, bacterial, and viral infections. One mechanism that has been proposed to account for this difference is the immunocompetence handicap model, which posits that the greater infectious disease burden in males is due to testosterone, which drives the development of secondary male sex characteristics at the expense of suppressing immunity. However, emerging data suggest that cell-intrinsic (chromosome X and Y) sex-specific factors also may contribute to the sex differences in infectious disease burden. Using a murine model of influenza A virus (IAV) infection and a panel of chromosome Y (ChrY) consomic strains on the C57BL/6J background, we present data showing that genetic variation in ChrY influences IAV pathogenesis in males. Specific ChrY variants increase susceptibility to IAV in males and augment pathogenic immune responses in the lung, including activation of proinflammatory IL-17-producing γδ T cells, without affecting viral replication. In addition, susceptibility to IAV segregates independent of copy number variation in multicopy ChrY gene families that influence susceptibility to other immunopathological phenotypes, including survival after infection with coxsackievirus B3. These results demonstrate a critical role for genetic variation in ChrY in regulating susceptibility to infectious disease.


chromosome Y; genetic variation; infectious disease; influenza A virus; sex

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