Pre-infection antiviral innate immunity contributes to sex differences in SARS-CoV-2 infection

Natalie Sauerwald, Zijun Zhang, Irene Ramos, Venugopalan D. Nair, Alessandra Soares-Schanoski, Yongchao Ge, Weiguang Mao, Hala Alshammary, Ana S. Gonzalez-Reiche, Adriana van de Guchte, Carl W. Goforth, Rhonda A. Lizewski, Stephen E. Lizewski, Mary Anne S. Amper, Mital Vasoya, Nitish Seenarine, Kristy Guevara, Nada Marjanovic, Clare M. Miller, German NudelmanMegan A. Schilling, Rachel S.G. Sealfon, Michael S. Termini, Sindhu Vangeti, Dawn L. Weir, Elena Zaslavsky, Maria Chikina, Ying Nian Wu, Harm Van Bakel, Andrew G. Letizia, Stuart C. Sealfon, Olga G. Troyanskaya

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Male sex is a major risk factor for SARS-CoV-2 infection severity. To understand the basis for this sex difference, we studied SARS-CoV-2 infection in a young adult cohort of United States Marine recruits. Among 2,641 male and 244 female unvaccinated and seronegative recruits studied longitudinally, SARS-CoV-2 infections occurred in 1,033 males and 137 females. We identified sex differences in symptoms, viral load, blood transcriptome, RNA splicing, and proteomic signatures. Females had higher pre-infection expression of antiviral interferon-stimulated gene (ISG) programs. Causal mediation analysis implicated ISG differences in number of symptoms, levels of ISGs, and differential splicing of CD45 lymphocyte phosphatase during infection. Our results indicate that the antiviral innate immunity set point causally contributes to sex differences in response to SARS-CoV-2 infection. A record of this paper's transparent peer review process is included in the supplemental information.

Original languageEnglish (US)
Pages (from-to)924-931.e4
JournalCell Systems
Issue number11
StatePublished - Nov 16 2022

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Cell Biology
  • Histology


  • COVID-19
  • SARS-CoV-2
  • alternative splicing
  • causal mediation
  • differential expression
  • interferon-stimulated genes
  • sex differences
  • viral infection


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