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Sex differences in immune responses that underlie COVID-19 disease outcomes

Author

Listed:
  • Takehiro Takahashi

    (Yale University School of Medicine)

  • Mallory K. Ellingson

    (Yale School of Public Health)

  • Patrick Wong

    (Yale University School of Medicine)

  • Benjamin Israelow

    (Yale University School of Medicine
    Yale University School of Medicine)

  • Carolina Lucas

    (Yale University School of Medicine)

  • Jon Klein

    (Yale University School of Medicine)

  • Julio Silva

    (Yale University School of Medicine)

  • Tianyang Mao

    (Yale University School of Medicine)

  • Ji Eun Oh

    (Yale University School of Medicine)

  • Maria Tokuyama

    (Yale University School of Medicine)

  • Peiwen Lu

    (Yale University School of Medicine)

  • Arvind Venkataraman

    (Yale University School of Medicine)

  • Annsea Park

    (Yale University School of Medicine)

  • Feimei Liu

    (Yale University School of Medicine
    Yale School of Engineering & Applied Science)

  • Amit Meir

    (Yale University)

  • Jonathan Sun

    (Yale University School of Medicine)

  • Eric Y. Wang

    (Yale University School of Medicine)

  • Arnau Casanovas-Massana

    (Yale School of Public Health)

  • Anne L. Wyllie

    (Yale School of Public Health)

  • Chantal B. F. Vogels

    (Yale School of Public Health)

  • Rebecca Earnest

    (Yale School of Public Health)

  • Sarah Lapidus

    (Yale School of Public Health)

  • Isabel M. Ott

    (Yale School of Public Health
    Yale University)

  • Adam J. Moore

    (Yale School of Public Health)

  • Albert Shaw

    (Yale University School of Medicine)

  • John B. Fournier

    (Yale University School of Medicine)

  • Camila D. Odio

    (Yale University School of Medicine)

  • Shelli Farhadian

    (Yale University School of Medicine)

  • Charles Cruz

    (Yale University School of Medicine)

  • Nathan D. Grubaugh

    (Yale School of Public Health)

  • Wade L. Schulz

    (Yale University School of Medicine
    Yale-New Haven Hospital)

  • Aaron M. Ring

    (Yale University School of Medicine)

  • Albert I. Ko

    (Yale School of Public Health)

  • Saad B. Omer

    (Yale School of Public Health
    Yale University School of Medicine
    Yale University
    Yale University)

  • Akiko Iwasaki

    (Yale University School of Medicine
    Howard Hughes Medical Institute)

Abstract

There is increasing evidence that coronavirus disease 2019 (COVID-19) produces more severe symptoms and higher mortality among men than among women1–5. However, whether immune responses against severe acute respiratory syndrome coronavirus (SARS-CoV-2) differ between sexes, and whether such differences correlate with the sex difference in the disease course of COVID-19, is currently unknown. Here we examined sex differences in viral loads, SARS-CoV-2-specific antibody titres, plasma cytokines and blood-cell phenotyping in patients with moderate COVID-19 who had not received immunomodulatory medications. Male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. By contrast, female patients had more robust T cell activation than male patients during SARS-CoV-2 infection. Notably, we found that a poor T cell response negatively correlated with patients’ age and was associated with worse disease outcome in male patients, but not in female patients. By contrast, higher levels of innate immune cytokines were associated with worse disease progression in female patients, but not in male patients. These findings provide a possible explanation for the observed sex biases in COVID-19, and provide an important basis for the development of a sex-based approach to the treatment and care of male and female patients with COVID-19.

Suggested Citation

  • Takehiro Takahashi & Mallory K. Ellingson & Patrick Wong & Benjamin Israelow & Carolina Lucas & Jon Klein & Julio Silva & Tianyang Mao & Ji Eun Oh & Maria Tokuyama & Peiwen Lu & Arvind Venkataraman & , 2020. "Sex differences in immune responses that underlie COVID-19 disease outcomes," Nature, Nature, vol. 588(7837), pages 315-320, December.
  • Handle: RePEc:nat:nature:v:588:y:2020:i:7837:d:10.1038_s41586-020-2700-3
    DOI: 10.1038/s41586-020-2700-3
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    Cited by:

    1. Juliana Lapa & Davi Rosa & João Pedro Lima Mendes & Rodolfo Deusdará & Gustavo Adolfo Sierra Romero, 2023. "Prevalence and Associated Factors of Post-COVID-19 Syndrome in a Brazilian Cohort after 3 and 6 Months of Hospital Discharge," IJERPH, MDPI, vol. 20(1), pages 1-12, January.
    2. Shelly J. Robertson & Olivia Bedard & Kristin L. McNally & Carl Shaia & Chad S. Clancy & Matthew Lewis & Rebecca M. Broeckel & Abhilash I. Chiramel & Jeffrey G. Shannon & Gail L. Sturdevant & Rebecca , 2023. "Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Danielsen, Ann Caroline & Lee, Katharine MN & Boulicault, Marion & Rushovich, Tamara & Gompers, Annika & Tarrant, Amelia & Reiches, Meredith & Shattuck-Heidorn, Heather & Miratrix, Luke W. & Richardso, 2022. "Sex disparities in COVID-19 outcomes in the United States: Quantifying and contextualizing variation," Social Science & Medicine, Elsevier, vol. 294(C).
    4. Sunil K. Ahuja & Muthu Saravanan Manoharan & Grace C. Lee & Lyle R. McKinnon & Justin A. Meunier & Maristella Steri & Nathan Harper & Edoardo Fiorillo & Alisha M. Smith & Marcos I. Restrepo & Anne P. , 2023. "Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection," Nature Communications, Nature, vol. 14(1), pages 1-31, December.
    5. Jia Wei & Philippa C. Matthews & Nicole Stoesser & Thomas Maddox & Luke Lorenzi & Ruth Studley & John I. Bell & John N. Newton & Jeremy Farrar & Ian Diamond & Emma Rourke & Alison Howarth & Brian D. M, 2021. "Anti-spike antibody response to natural SARS-CoV-2 infection in the general population," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    6. Simona Bignami-Van Assche & Daniela Ghio, 2022. "Comparing COVID-19 fatality across countries: a synthetic demographic indicator," Journal of Population Research, Springer, vol. 39(4), pages 513-525, December.
    7. Katsuhiko Suzuki & Amir Hossein Ahmadi Hekmatikar & Shadi Jalalian & Shaghayegh Abbasi & Elmira Ahmadi & Abdolreza Kazemi & Ruheea Taskin Ruhee & Kayvan Khoramipour, 2022. "The Potential of Exerkines in Women’s COVID-19: A New Idea for a Better and More Accurate Understanding of the Mechanisms behind Physical Exercise," IJERPH, MDPI, vol. 19(23), pages 1-21, November.
    8. Viet-Thi Tran & Raphaël Porcher & Isabelle Pane & Philippe Ravaud, 2022. "Course of post COVID-19 disease symptoms over time in the ComPaRe long COVID prospective e-cohort," Nature Communications, Nature, vol. 13(1), pages 1-6, December.
    9. Dominik Menges & Kyra D. Zens & Tala Ballouz & Nicole Caduff & Daniel Llanas-Cornejo & Hélène E. Aschmann & Anja Domenghino & Céline Pellaton & Matthieu Perreau & Craig Fenwick & Giuseppe Pantaleo & C, 2022. "Heterogenous humoral and cellular immune responses with distinct trajectories post-SARS-CoV-2 infection in a population-based cohort," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Nathália Mariana Santos Sansone & Letícia Rogini Pereira & Matheus Negri Boschiero & Felipe Eduardo Valencise & Andréa Melo Alexandre Fraga & Fernando Augusto Lima Marson, 2022. "Characterization of Clinical Features of Hospitalized Patients Due to the SARS-CoV-2 Infection in the Absence of Comorbidities Regarding the Sex: An Epidemiological Study of the First Year of the Pand," IJERPH, MDPI, vol. 19(15), pages 1-20, July.
    11. Abdulaziz Alqahtani & Edrous Alamer & Mushtaq Mir & Ali Alasmari & Mohammed Merae Alshahrani & Mohammed Asiri & Irfan Ahmad & Abdulaziz Alhazmi & Abdullah Algaissi, 2022. "Bacterial Coinfections Increase Mortality of Severely Ill COVID-19 Patients in Saudi Arabia," IJERPH, MDPI, vol. 19(4), pages 1-11, February.
    12. Cássia da Luz Goulart & Guilherme Peixoto Tinoco Arêas & Mauricio Milani & Fernanda Facioli dos Reis Borges & Juliana Ribeiro Magalhães & Guilherme Dionir Back & Audrey Borghi-Silva & Luciano Fonseca , 2024. "Sex-Based Differences in Pulmonary Function and Cardiopulmonary Response 30 Months Post-COVID-19: A Brazilian Multicentric Study," IJERPH, MDPI, vol. 21(10), pages 1-10, September.
    13. Peter Radvak & Hyung-Joon Kwon & Martina Kosikova & Uriel Ortega-Rodriguez & Ruoxuan Xiang & Je-Nie Phue & Rong-Fong Shen & James Rozzelle & Neeraj Kapoor & Taylor Rabara & Jeff Fairman & Hang Xie, 2021. "SARS-CoV-2 B.1.1.7 (alpha) and B.1.351 (beta) variants induce pathogenic patterns in K18-hACE2 transgenic mice distinct from early strains," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    14. Sarah Hawkes & Athena Pantazis & Anna Purdie & Abhishek Gautam & Sylvia Kiwuwa-Muyingo & Kent Buse & Sonja Tanaka & Kakoli Borkotoky & Sneha Sharma & Ravi Verma, 2022. "Sex-disaggregated data matters: tracking the impact of COVID-19 on the health of women and men," Economia Politica: Journal of Analytical and Institutional Economics, Springer;Fondazione Edison, vol. 39(1), pages 55-73, April.

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