Sex differences in adenosine deaminase activity associate with disparities in SARS-CoV-2 innate immunity

Priyanka Saminathan; Ian T Mathews; Ahmad Alimadadi; Kai Fung; Kiyokazu Kakugawa; Leo A B Joosten; Mihai G Netea; Mohit Jain; Susan Cheng; Catherine C Hedrick; Sonia Sharma

doi:10.1016/j.isci.2025.112418

Sex differences in adenosine deaminase activity associate with disparities in SARS-CoV-2 innate immunity

iScience. 2025 Apr 14;28(5):112418. doi: 10.1016/j.isci.2025.112418. eCollection 2025 May 16.

Authors

Priyanka Saminathan¹, Ian T Mathews^{1

2}, Ahmad Alimadadi^{1

3}, Kai Fung¹, Kiyokazu Kakugawa⁴, Leo A B Joosten^{5

6}, Mihai G Netea^{5

7}, Mohit Jain⁸, Susan Cheng⁹, Catherine C Hedrick³, Sonia Sharma^{1

4}

Affiliations

¹ Center for Sex Differences in the Immune System, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
² Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
³ Immunology Center of Georgia and Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.
⁴ Laboratory for Inflammatory Immune Metabolism, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa 230-0045, Japan.
⁵ Department of Internal Medicine and Radboud Community Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
⁶ Department of Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania.
⁷ Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn 53127, Germany.
⁸ Sapient Bioanalytics, San Diego, CA 92121, USA.
⁹ Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Abstract

Females demonstrate elevated type-I interferon production and a stronger antiviral immune response; however, the mechanisms underlying sex-based differences in antiviral immunity are incompletely understood. We previously reported that low adenosine deaminase (ADA) activity perturbs the methylation-based transcriptional silencing of endogenous retroviral elements (hERV), which stimulates IFN-Stimulated Genes (ISG) and primes antiviral immunity. Here we demonstrate lower ADA activity in females compared to their male counterparts, which correlated with higher hERV and ISG expression in female lungs. Sex differences in ADA2 were linked to the number and expression profiles of blood and lung-derived monocyte populations. Single-cell RNA sequencing of respiratory cells from patients with COVID-19 showed a significant female bias in hERV-ISG signatures, and implicated IL-18 as a driver of sex-specific ADA2 expression. Observations in healthy and COVID-19 cohorts indicate that higher ADA activity is associated with suppressed antiviral innate immunity in the male respiratory tract, which may drive adverse COVID-19 outcomes.

Keywords: Immunology; Virology.