Sex differences in COVID-19: from animal models to clinical data

Sabra L. Klein

W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, MD, USA


Around the world, while males and females are equally likely to test positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), males are significantly more likely to be hospitalized, admitted into intensive care units, and die from the 2019 coronavirus disease (COVID-19).1-3 Although globally there are similar proportions of males and females testing positive for SARS-CoV-2, there are a number of gender-associated differences with behavior (e.g., acceptance of public health measures that limit virus spread),4 occupations,5 and access to healthcare for testing6 that contribute to regional differences in SARS-CoV-2 exposure between the sexes.

Gender differences (i.e., social construct that defines norms for men and women) are separate from but complementary to biological sex differences that are mediated by sex chromosome complement, differential reproductive tissues, and differential concentrations of sex steroid hormones. The enrichment of the X chromosome for immune response genes,7 combined with the presence of sex steroid hormone receptors on diverse innate and adaptive immune cells and the presence of hormone response elements in the promotors of numerous immune response genes can give rise to sex differences in immunity to viruses.8 Consequently, there are sex differences in immunity to SARS-CoV-2, control of virus replication, development of immunopathologies, and long-term protection.9 Males consistently have greater proinflammatory cytokine production (e.g., IL-6 and CRP) than females in the context of COVID-19.3 Older males with COVID-19 have lower CD8+ T cell activity (e.g., IFN-g production and proliferation),10 but have greater antiviral antibody responses11 than females.

Animal models are integral for studying the impact of biological sex on the pathogenesis of SARS-CoV-2. In golden Syrian hamsters infected with a clinical isolate of SARS-CoV-2, male hamsters experience greater morbidity and develop more extensive pneumonia than females.12 Treatment of male hamsters with estradiol does not alter pulmonary damage. During the recovery phase of infection, females mount greater antibody responses in both plasma and respiratory tissues. The development of an animal model to study COVID-19 sex differences will allow for a greater mechanistic understanding of the SARS-CoV-2 associated sex differences seen in the human population.

Keywords. SARS-CoV-2, golden Syrian hamsters, electronic health records, convalescent plasma.

References

1. GlobalHealth5050. The sex, gender and COVID-19 project 2020 [updated November 30, 2020; cited 2020 December 28]. Available from: https://globalhealth5050.org/the-sex-gender-and-covid-19-project/.

2. Peckham H, de Gruijter NM, Raine C, Radziszewska A, Ciurtin C, Wedderburn LR, et al. Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat Commun. 2020;11(1):6317.

3. Scully EP, Schumock G, Fu M, Massaccesi G, Muschelli J, Betz J, et al. Sex and gender differences in COVID testing, hospital admission, presentation, and drivers of severe outcomes in the DC/Maryland region. medRxiv. 2021:2021.04.05.21253827.

4. Galasso V, Pons V, Profeta P, Becher M, Brouard S, Foucault M. Gender differences in COVID-19 attitudes and behavior: panel evidence from eight countries. Proc Natl Acad Sci USA. 2020;117(44):27285-91.

5. Wenham C, Smith J, Morgan R, Gender and COVID-19 Working Group. COVID-19: the gendered impacts of the outbreak. Lancet. 2020;395(10227):846-8.

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7. Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol. 2008;8(9):737-44.

8. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626-38.

9. Scully EP, Haverfield J, Ursin RL, Tannenbaum C, Klein SL. Considering how biological sex impacts immune responses and COVID-19 outcomes. Nat Rev Immunol. 2020;20:442-7.

10. Takahashi T, Ellingson MK, Wong P, Israelow B, Lucas C, Klein J, et al. Sex differences in immune responses that underlie COVID-19 disease outcomes. Nature. 2020;588(7837):315-20.

11. Klein SL, Pekosz A, Park HS, Ursin RL, Shapiro JR, Benner SE, et al. Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma donor population. J Clin Invest. 2020;130(11):6141-50.

12. Dhakal S, Ruiz-Bedoya CA, Zhou R, Creisher PS, Villano JS, Littlefield K, et al. Sex differences in lung imaging and SARS-CoV-2 antibody responses in a COVID-19 golden Syrian hamster model. bioRxiv. 2021:2021.04.02.438292.

Conflict of interest: the Author declares that she has no competing interests.

Ethics approval: the Johns Hopkins IRB and ACUC approved all research presented.

Funding: The NIH/NCI COVID-19 Serology Center of Excellence U54CA260492 and the NIH/ORWH/NIA Specialized Center of Research Excellence in Sex Differences U54AG062333.

Correspondence to:

Sabra L. Klein

W. Harry Feinstone Department of Molecular Microbiology and Immunology

Johns Hopkins Bloomberg School of Public Health

615 N. Wolfe Street

Room W2118

Baltimore, Maryland 21205, USA

email: sklein2@jhu.edu