Yin Kailin, Peluso Michael J, Luo Xiaoyu, Thomas Reuben, Shin Min-Gyoung, Neidleman Jason, Andrew Alicer, Young Kyrlia, Ma Tongcui, Hoh Rebecca, Anglin Khamal, Huang Beatrice, Argueta Urania, Lopez Monica, Valdivieso Daisy, Asare Kofi, Deveau Tyler-Marie, Munter Sadie E, Ibrahim Rania, Ständker Ludger, Lu Scott, Goldberg Sarah A, Lee Sulggi A, Lynch Kara L, Kelly J Daniel, Martin Jeffrey N, Münch Jan, Deeks Steven G, Henrich Timothy J, Roan Nadia R
Gladstone Institutes, University of California, San Francisco, USA.
Department of Urology, University of California, San Francisco, USA.
bioRxiv. 2023 Aug 4:2023.02.09.527892. doi: 10.1101/2023.02.09.527892.
Long COVID (LC), a type of post-acute sequelae of SARS-CoV-2 infection (PASC), occurs after at least 10% of SARS-CoV-2 infections, yet its etiology remains poorly understood. Here, we used multiple "omics" assays (CyTOF, RNAseq/scRNAseq, Olink) and serology to deeply characterize both global and SARS-CoV-2-specific immunity from blood of individuals with clear LC and non-LC clinical trajectories, 8 months following infection and prior to receipt of any SARS-CoV-2 vaccine. Our analysis focused on deep phenotyping of T cells, which play important roles in immunity against SARS-CoV-2 yet may also contribute to COVID-19 pathogenesis. Our findings demonstrate that individuals with LC exhibit systemic inflammation and immune dysregulation. This is evidenced by global differences in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations in cytolytic subsets. Individuals with LC harbored increased frequencies of CD4+ T cells poised to migrate to inflamed tissues, and exhausted SARS-CoV-2-specific CD8+ T cells. They also harbored significantly higher levels of SARS-CoV-2 antibodies, and in contrast to non-LC individuals, exhibited a mis-coordination between their SARS-CoV-2-specific T and B cell responses. RNAseq/scRNAseq and Olink analyses similarly revealed immune dysregulatory mechanisms, along with non-immune associated perturbations, in individuals with LC. Collectively, our data suggest that proper crosstalk between the humoral and cellular arms of adaptive immunity has broken down in LC, and that this, perhaps in the context of persistent virus, leads to the immune dysregulation, inflammation, and clinical symptoms associated with this debilitating condition.
长新冠（LC）是新冠病毒2型感染（SARS-CoV-2）的一种急性后遗症（PASC），至少10%的SARS-CoV-2感染后会出现，但对其病因仍知之甚少。在这里，我们使用了多种“组学”检测方法（质谱流式细胞术、RNA测序/单细胞RNA测序、邻接延伸分析）和血清学，对感染8个月后且在接种任何SARS-CoV-2疫苗之前，具有明确长新冠和非长新冠临床病程的个体血液中的整体免疫和SARS-CoV-2特异性免疫进行了深入表征。我们的分析重点是T细胞的深度表型分析，T细胞在抗SARS-CoV-2免疫中起重要作用，但也可能导致新冠病毒疾病的发病机制。我们的研究结果表明，长新冠患者表现出全身炎症和免疫失调。这表现为T细胞亚群分布的整体差异，暗示着持续的免疫反应，以及细胞溶解亚群中的性别特异性扰动。长新冠患者中准备迁移至炎症组织的CD4+T细胞频率增加，且SARS-CoV-2特异性CD8+T细胞耗竭。他们还具有显著更高水平的SARS-CoV-2抗体，并且与非长新冠个体相比，其SARS-CoV-2特异性T细胞和B细胞反应之间存在失调。RNA测序/单细胞RNA测序和邻接延伸分析同样揭示了长新冠患者的免疫失调机制以及非免疫相关的扰动。总体而言，我们的数据表明，适应性免疫的体液免疫和细胞免疫分支之间的正常相互作用在长新冠中已经瓦解，这可能在持续病毒的背景下，导致了与这种使人衰弱的疾病相关的免疫失调、炎症和临床症状。
