Sex disparities in influenza: A multiscale network analysis
Chang Wang,
Lauren P. Lashua,
Chalise E. Carter,
Scott K. Johnson,
Minghui Wang,
Ted M. Ross,
Elodie Ghedin,
Bin Zhang,
Christian V. Forst
Affiliations
Chang Wang
Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
Lauren P. Lashua
Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA
Chalise E. Carter
Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA
Scott K. Johnson
Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA
Minghui Wang
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1498, New York, NY 10029-6574, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029-6501, USA
Ted M. Ross
Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA; Department of Infectious Diseases, Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA
Elodie Ghedin
Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY, USA; Systems Genomics Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD, USA
Bin Zhang
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1498, New York, NY 10029-6574, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029-6501, USA; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1677, New York, NY 10029-6574, USA
Christian V. Forst
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1498, New York, NY 10029-6574, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029-6501, USA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1498, New York, NY 10029-6574; Corresponding author
Summary: Sex differences in the pathogenesis of infectious diseases because of differential immune responses between females and males have been well-documented for multiple pathogens. However, the molecular mechanism underlying the observed sex differences in influenza virus infection remains poorly understood. In this study, we used a network-based approach to characterize the blood transcriptome collected over the course of infection with influenza A virus from female and male ferrets to dissect sex-biased gene expression. We identified significant differences in the temporal dynamics and regulation of immune responses between females and males. Our results elucidate sex-differentiated pathways involved in the unfolded protein response (UPR), lipid metabolism, and inflammatory responses, including a female-biased IRE1/XBP1 activation and male-biased crosstalk between metabolic reprogramming and IL-1 and AP-1 pathways. Overall, our study provides molecular insights into sex differences in transcriptional regulation of immune responses and contributes to a better understanding of sex biases in influenza pathogenesis.
