Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
Hawaii Center for AIDS, University of Hawai'i at Mānoa, Honolulu, HI, United States.
Front Immunol. 2024 Jan 8;14:1268510. doi: 10.3389/fimmu.2023.1268510. eCollection 2023.
Although our understanding of the immunopathology and subsequent risk and severity of COVID-19 disease is evolving, a detailed account of immune responses that contribute to the long-term consequences of pulmonary complications in COVID-19 infection remains unclear. Few studies have detailed the immune and cytokine profiles associated with post-acute sequelae of SARS-CoV-2 infection (PASC) with persistent pulmonary symptoms. The dysregulation of the immune system that drives pulmonary sequelae in COVID-19 survivors and PASC sufferers remains largely unknown.
To characterize the immunological features of pulmonary PASC (PPASC), we performed droplet-based single-cell RNA sequencing (scRNA-seq) to study the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from a participant naïve to SARS-CoV-2 (Control) (n=1) and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC) (n=2). After integrating scRNA-seq data with a naïve participant from a published dataset, 11 distinct cell populations were identified based on the expression of canonical markers. The proportion of myeloid-lineage cells ([MLCs]; CD14/CD16monocytes, and dendritic cells) was increased in PPASC (n=2) compared to controls (n=2). MLCs from PPASC displayed up-regulation of genes associated with pulmonary symptoms/fibrosis, while glycolysis metabolism-related genes were downregulated. Similarly, pathway analysis showed that fibrosis-related (, , and ) and cell death pathways were up-regulated, but immune pathways were down-regulated in PPASC. Further comparison of PPASC with scRNA-seq data with Severe COVID-19 (n=4) data demonstrated enrichment of fibrotic transcriptional signatures. In PPASC, we observed interactive ligand-receptor pairs among MLCs, and network modules in CD14 (cluster 4) and CD16 (Cluster 5) monocytes displayed a significant enrichment for biological pathways linked to adverse COVID-19 outcomes, fibrosis, and angiogenesis. Further analysis revealed a distinct metabolic alteration in MLCs with a down-regulation of glycolysis/gluconeogenesis in PPASC compared to SARS-CoV-2 naïve samples.
Analysis of a small scRNA-seq dataset demonstrated alterations in the immune response and cellular landscape in PPASC. The presence of elevated MLC levels and their corresponding gene signatures associated with fibrosis, immune response suppression, and altered metabolic states suggests a potential role in PPASC development.
尽管我们对 COVID-19 疾病的免疫病理学以及随后的风险和严重程度的理解在不断发展，但对于导致 COVID-19 感染后肺部并发症的长期后果的免疫反应仍不清楚。很少有研究详细描述与 SARS-CoV-2 感染后急性后遗症（PASC）持续肺部症状相关的免疫和细胞因子特征。在 COVID-19 幸存者和 PASC 患者中驱动肺部后遗症的免疫系统失调在很大程度上仍然未知。
为了表征肺部 PASC（PPASC）的免疫学特征，我们进行了基于液滴的单细胞 RNA 测序（scRNA-seq），以研究对 SARS-CoV-2 无反应的参与者（对照）（n=1）和感染 SARS-CoV-2 并伴有慢性肺部症状（PPASC）（n=2）的外周血单核细胞（PBMC）的转录组谱。将 scRNA-seq 数据与来自已发表数据集的无反应参与者整合后，根据典型标志物的表达，确定了 11 个不同的细胞群。与对照（n=2）相比，PPASC（n=2）中的髓系细胞群（[MLCs]；CD14/CD16 单核细胞和树突状细胞）比例增加。PPASC 的 MLC 显示与肺部症状/纤维化相关的基因上调，而糖酵解代谢相关基因下调。同样，途径分析表明，纤维化相关（、和）和细胞死亡途径上调，但 PPASC 中的免疫途径下调。进一步将 PPASC 与严重 COVID-19（n=4）的 scRNA-seq 数据进行比较，显示纤维化转录特征丰富。在 PPASC 中，我们观察到 MLC 之间的交互配体-受体对，并且 CD14（簇 4）和 CD16（簇 5）单核细胞中的网络模块显示出与不良 COVID-19 结局、纤维化和血管生成相关的生物途径的显著富集。进一步分析显示，与 SARS-CoV-2 无反应样本相比，PPASC 中 MLC 的代谢明显改变，糖酵解/糖异生下调。
对小型 scRNA-seq 数据集的分析表明，PPASC 中的免疫反应和细胞景观发生了改变。高水平 MLC 及其与纤维化、免疫反应抑制和代谢状态改变相关的特征的存在表明其在 PPASC 发展中的潜在作用。
