Saminathan Priyanka, Mathews Ian T, Alimadadi Ahmad, Fung Kai, Kakugawa Kiyokazu, Joosten Leo A B, Netea Mihai G, Jain Mohit, Cheng Susan, Hedrick Catherine C, Sharma Sonia
Center for Sex Differences in the Immune System, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
iScience. 2025 Apr 14;28(5):112418. doi: 10.1016/j.isci.2025.112418. eCollection 2025 May 16.
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.
女性表现出I型干扰素产生增加和更强的抗病毒免疫反应；然而，抗病毒免疫中基于性别的差异背后的机制尚未完全明确。我们之前报道过低腺苷脱氨酶（ADA）活性会扰乱内源性逆转录病毒元件（hERV）基于甲基化的转录沉默，从而刺激干扰素刺激基因（ISG）并启动抗病毒免疫。在这里，我们证明女性的ADA活性低于男性，这与女性肺部更高的hERV和ISG表达相关。ADA2的性别差异与血液和肺来源的单核细胞群体的数量和表达谱有关。对COVID-19患者呼吸细胞的单细胞RNA测序显示，hERV-ISG特征在女性中存在显著偏差，并表明IL-18是性别特异性ADA2表达的驱动因素。在健康人群和COVID-19队列中的观察结果表明，较高的ADA活性与男性呼吸道中抗病毒先天免疫的抑制有关，这可能导致COVID-19的不良后果。
