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 Nudelman; Megan 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

doi:10.1016/j.cels.2022.10.005

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

Cell Syst. 2022 Nov 16;13(11):924-931.e4. doi: 10.1016/j.cels.2022.10.005. Epub 2022 Nov 1.

Authors

Natalie Sauerwald¹, Zijun Zhang¹, Irene Ramos², Venugopalan D Nair², Alessandra Soares-Schanoski², Yongchao Ge², Weiguang Mao³, Hala Alshammary⁴, Ana S Gonzalez-Reiche⁵, Adriana van de Guchte⁵, Carl W Goforth⁶, Rhonda A Lizewski⁷, Stephen E Lizewski⁷, Mary Anne S Amper², Mital Vasoya², Nitish Seenarine², Kristy Guevara², Nada Marjanovic², Clare M Miller², German Nudelman², Megan A Schilling⁶, Rachel S G Sealfon¹, Michael S Termini⁸, Sindhu Vangeti², Dawn L Weir⁶, Elena Zaslavsky², Maria Chikina³, Ying Nian Wu⁹, Harm Van Bakel⁵, Andrew G Letizia⁶, Stuart C Sealfon¹⁰, Olga G Troyanskaya¹¹

Affiliations

¹ Center for Computational Biology, Flatiron Institute, New York, NY 10010, USA.
² Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³ Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
⁴ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁶ Naval Medical Research Center, Silver Spring, MD 20910, USA.
⁷ Naval Medical Research Unit 6, Lima 34031, Peru.
⁸ Navy Medicine Readiness and Training Command Beaufort, Beaufort, SC 29902, USA.
⁹ Department of Statistics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: stuart.sealfon@mssm.edu.
¹¹ Center for Computational Biology, Flatiron Institute, New York, NY 10010, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08540, USA; Department of Computer Science, Princeton University, Princeton, NJ 08540, USA. Electronic address: ogt@genomics.princeton.edu.

Abstract

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.

Keywords: COVID-19; SARS-CoV-2; alternative splicing; causal mediation; differential expression; interferon-stimulated genes; sex differences; viral infection.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

COVID-19* / immunology
Female
Humans
Immunity, Innate*
Interferons
Male
Proteomics
SARS-CoV-2
Sex Characteristics*
Young Adult

Substances

Interferons

Grants and funding

R01 GM071966/GM/NIGMS NIH HHS/United States