Sex differences have been observed in acute coronavirus disease 2019 (COVID-19) and Long Covid (LC) outcomes, with greater disease severity and mortality during acute infection in males and greater proportions of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to LC pathogenesis. To investigate the immunologic underpinnings of LC development and symptom persistence, we performed multiomic analyses on blood samples obtained during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 3 and 12 months after infection in a cohort of 45 participants who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Males who would later develop LC exhibited increases in transforming growth factor–β (TGF-β) signaling during acute infection, whereas females who would go on to develop LC had reduced TGFB1 expression. Females who developed LC demonstrated increased expression of XIST , an RNA gene implicated in autoimmunity, during acute infection compared with females who recovered. Many immune features of LC were also conserved across sexes, such as alterations in monocyte phenotype and activation state. Nuclear factor κB (NF-κB) transcription factors were up-regulated in many cell types at acute and convalescent time points. Those with ongoing LC demonstrated reduced ETS1 expression across lymphocyte subsets and elevated intracellular IL-4 in T cell subsets, suggesting that ETS1 alterations may drive aberrantly elevated T helper cell 2–like responses in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.

中文翻译：

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Long Covid 发展、症状持续和消退的性别差异和免疫相关性


在 2019 年急性冠状病毒病 （COVID-19） 和长期 Covid （LC） 结局中观察到性别差异，男性急性感染期间的疾病严重程度和死亡率更高，女性发生 LC 的比例更高。我们假设性别特异性免疫失调有助于 LC 发病机制。为了研究 LC 发展和症状持续的免疫学基础，我们对急性严重急性呼吸系统综合症冠状病毒 2 （SARS-CoV-2） 感染期间以及感染后 3 个月和 12 个月获得的血液样本进行了多组学分析，该队列由 45 名发生 LC 或康复的参与者组成。几种性别特异性免疫通路与 LC 相关。在急性感染期间，后来发展为 LC 的男性表现出转化生长因子-β （TGF-β） 信号的增加，而继续发展为 LC 的女性则降低了 TGFB1 表达。与康复的女性相比，发生 LC 的女性在急性感染期间表现出 XIST 的表达增加，XIST 是一种与自身免疫有关的 RNA 基因。LC 的许多免疫特征在性别之间也是保守的，例如单核细胞表型和激活状态的改变。核因子 κB （NF-κB） 转录因子在许多细胞类型中在急性期和恢复期上调。那些进行 LC 的患者显示 ETS1 在淋巴细胞亚群中的表达降低，在 T 细胞亚群中细胞内 IL-4 升高，这表明 ETS1 改变可能导致 LC 中辅助性 T 细胞 2 样反应异常升高。总而言之，本研究描述了 LC 的多种先天性和适应性免疫相关性，其中一些因性别而异，并为追求量身定制的疗法提供了见解。