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

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.