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

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.

SUBMITTER: Sauerwald N

PROVIDER: S-EPMC9623453 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Sauerwald Natalie N Zhang Zijun Z Ramos Irene I Nair Venugopalan D VD Soares-Schanoski Alessandra A Ge Yongchao Y Mao Weiguang W Alshammary Hala H Gonzalez-Reiche Ana S AS van de Guchte Adriana A Goforth Carl W CW Lizewski Rhonda A RA Lizewski Stephen E SE Amper Mary Anne S MAS Vasoya Mital M Seenarine Nitish N Guevara Kristy K Marjanovic Nada N Miller Clare M CM Nudelman German G Schilling Megan A MA Sealfon Rachel S G RSG Termini Michael S MS Vangeti Sindhu S Weir Dawn L DL Zaslavsky Elena E Chikina Maria M Wu Ying Nian YN Van Bakel Harm H Letizia Andrew G AG Sealfon Stuart C SC Troyanskaya Olga G OG

Cell systems 20221101 11

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 p ...[more]

PMID: 36323307

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Project description:A large portion of the heterogeneity in coronavirus disease 2019 (COVID-19) susceptibility and severity of illness (SOI) remains poorly understood. Recent evidence suggests that SARS-CoV-2 infection-associated damage to alveolar epithelial type 2 cells (AT2s) in the distal lung may directly contribute to disease severity and poor prognosis in COVID-19 patients. Our in vitro modeling of SARS-CoV-2 infection in induced pluripotent stem cell (iPSC)-derived AT2s from 10 different individuals showed interindividual variability in infection susceptibility and the postinfection cellular viral load. To understand the underlying mechanism of the AT2's capacity to regulate SARS-CoV-2 infection and cellular viral load, a genome-wide differential gene expression analysis between the mock and SARS-CoV-2 infection-challenged AT2s was performed. The 1393 genes, which were significantly (one-way ANOVA FDR-corrected p ≤ 0.05; FC abs ≥ 2.0) differentially expressed (DE), suggest significant upregulation of viral infection-related cellular innate immune response pathways (p-value ≤ 0.05; activation z-score ≥ 3.5), and significant downregulation of the cholesterol- and xenobiotic-related metabolic pathways (p-value ≤ 0.05; activation z-score ≤ -3.5). Whilst the effect of post-SARS-CoV-2 infection response on the infection susceptibility and postinfection viral load in AT2s is not clear, interestingly, pre-infection (mock-challenged) expression of 238 DE genes showed a high correlation with the postinfection SARS-CoV-2 viral load (FDR-corrected p-value ≤ 0.05 and r2-absolute ≥ 0.57). The 85 genes whose expression was negatively correlated with the viral load showed significant enrichment in viral recognition and cytokine-mediated innate immune GO biological processes (p-value range: 4.65 × 10-10 to 2.24 × 10-6). The 153 genes whose expression was positively correlated with the viral load showed significant enrichment in cholesterol homeostasis, extracellular matrix, and MAPK/ERK pathway-related GO biological processes (p-value range: 5.06 × 10-5 to 6.53 × 10-4). Overall, our results strongly suggest that AT2s' pre-infection innate immunity and metabolic state affect their susceptibility to SARS-CoV-2 infection and viral load.

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

Publications

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

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