TY - JOUR
T1 - Pre-infection antiviral innate immunity contributes to sex differences in SARS-CoV-2 infection
AU - Sauerwald, Natalie
AU - Zhang, Zijun
AU - Ramos, Irene
AU - Nair, Venugopalan D.
AU - Soares-Schanoski, Alessandra
AU - Ge, Yongchao
AU - Mao, Weiguang
AU - Alshammary, Hala
AU - Gonzalez-Reiche, Ana S.
AU - van de Guchte, Adriana
AU - Goforth, Carl W.
AU - Lizewski, Rhonda A.
AU - Lizewski, Stephen E.
AU - Amper, Mary Anne S.
AU - Vasoya, Mital
AU - Seenarine, Nitish
AU - Guevara, Kristy
AU - Marjanovic, Nada
AU - Miller, Clare M.
AU - Nudelman, German
AU - Schilling, Megan A.
AU - Sealfon, Rachel S.G.
AU - Termini, Michael S.
AU - Vangeti, Sindhu
AU - Weir, Dawn L.
AU - Zaslavsky, Elena
AU - Chikina, Maria
AU - Wu, Ying Nian
AU - Van Bakel, Harm
AU - Letizia, Andrew G.
AU - Sealfon, Stuart C.
AU - Troyanskaya, Olga G.
N1 - Funding Information:
We thank the Human Immuno Monitoring Core (HIMC) at Icahn School of Medicine at Mount Sinai for performing the proteomics OLINK assays. We thank the many US Navy corpsmen who assisted in the logistics and sample acquisition and the devoted Marine recruits who volunteered for this study. This study was approved by the Naval Medical Research Center (NMRC) institutional review board (IRB), protocol number NMRC.2020.0006, in compliance with all applicable US federal regulations governing the protection of human subjects. This study was funded by Defense Advanced Research Projects Agency contract number N6600119C4022 (S.C.S.), Defense Healthy Agency grant 9700130 through the Naval Medical Research Center (A.G.L.), National Institutes of Health grant R01GM071966 (O.G.T.), and Simons Foundation grant 395506 (O.G.T.). Conceptualization, Z.Z. N.S. O.G.T. and S.C.S.; investigation: I.R. A.S.S. V.D.N. M.A.S.A. M.V. N.S. K.G. N.M. C.M.M. S.V. R.S.G.S. H.A. A.S.G.-R. A.v.d.G. C.W.G. R.A.L. S.E.L. G.N. M.A.S. M.S.T. D.L.W. E.Z. and H.V.B.; resources: S.C.S.; data curation: Y.G.; methodology, Z.Z. N.S. and Y.N.W.; formal analysis, Z.Z. N.S. W.M. and M.C.; funding acquisition: A.G.L. S.C.S. and O.G.T.; project administration, A.G.L. S.C.S. and O.G.T.; supervision: S.C.S. and O.G.T.; writing – original draft, Z.Z. N.S. O.G.T. and S.C.S.; writing – review & editing, Z.Z. N.S. O.G.T. S.C.S. A.G.L. A.S.S. Y.G. W.M. and I.R. C.W.G. R.A.L. S.E.L. M.A.S. M.S.T. D.L.W. and A.G.L. are military service members or government service employees. This work was prepared as part of their official duties. Title 17, US Code §105 provides that copyright protection under this title is not available for any work of the US Government. Title 17, US code §101 defines a US Government work as a work prepared by a military service member or employee of the US Government as part of that person's official duties. The views expressed in the article are those of the authors and do not necessarily express the official policy and position of the US Navy, the Department of Defense, and the US Government or the institutions affiliated with the authors. O.G.T. is on the advisory board of Cell Systems.
Funding Information:
We thank the Human Immuno Monitoring Core (HIMC) at Icahn School of Medicine at Mount Sinai for performing the proteomics OLINK assays. We thank the many US Navy corpsmen who assisted in the logistics and sample acquisition and the devoted Marine recruits who volunteered for this study. This study was approved by the Naval Medical Research Center (NMRC) institutional review board (IRB), protocol number NMRC.2020.0006, in compliance with all applicable US federal regulations governing the protection of human subjects. This study was funded by Defense Advanced Research Projects Agency contract number N6600119C4022 (S.C.S.), Defense Healthy Agency grant 9700130 through the Naval Medical Research Center (A.G.L.), National Institutes of Health grant R01GM071966 (O.G.T.), and Simons Foundation grant 395506 (O.G.T.).
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/11/16
Y1 - 2022/11/16
N2 - 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.
AB - 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.
KW - COVID-19
KW - SARS-CoV-2
KW - alternative splicing
KW - causal mediation
KW - differential expression
KW - interferon-stimulated genes
KW - sex differences
KW - viral infection
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U2 - 10.1016/j.cels.2022.10.005
DO - 10.1016/j.cels.2022.10.005
M3 - Article
C2 - 36323307
AN - SCOPUS:85141230812
SN - 2405-4712
VL - 13
SP - 924-931.e4
JO - Cell Systems
JF - Cell Systems
IS - 11
ER -