Yoon Hyundong, Dean Logan S, Jiyarom Boonyanudh, Khadka Vedbar, Deng Youping, Nerurukar Vivek R, Chow Dominic C, Shikuma Cecilia M, Devendra Gehan, Koh Youngil, Park Juwon
bioRxiv. 2023 Aug 2:2023.07.31.551349. doi: 10.1101/2023.07.31.551349.
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 complication in COVID-19 infection remain unclear. Few studies have detailed the immune and cytokine profiles associated with post-acute sequalae of SARS-CoV-2 infection with persistent pulmonary symptoms (PPASC). However, 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 to study the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from participants naïve to SARS-CoV-2 (Control) and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC). We analyzed more than 34,139 PBMCs by integrating our dataset with previously reported control datasets (GSM4509024) cell distribution. In total, 11 distinct cell populations were identified based on the expression of canonical markers. The proportion of myeloid-lineage cells ([MLCs]; CD14 /CD16 monocytes and dendritic cells) was increased in PPASC compared to controls. 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. 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.
This study offers valuable insights into 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 their potential role as a driver of PPASC.
尽管我们对新冠病毒疾病的免疫病理学以及后续风险和严重程度的理解不断发展，但对于导致新冠病毒感染肺部并发症长期后果的免疫反应的详细情况仍不清楚。很少有研究详细描述与伴有持续性肺部症状的新冠病毒感染后急性后遗症（PPASC）相关的免疫和细胞因子谱。然而，驱动新冠病毒感染幸存者和PPASC患者肺部后遗症的免疫系统失调在很大程度上仍不为人知。
为了表征肺部PPASC的免疫学特征，我们进行了基于液滴的单细胞RNA测序，以研究未感染过新冠病毒（对照）和感染新冠病毒且有慢性肺部症状（PPASC）的参与者外周血单个核细胞（PBMC）的转录组谱。我们通过将我们的数据集与先前报道的对照数据集（GSM4509024）细胞分布进行整合，分析了超过34139个PBMC。基于典型标志物的表达，总共鉴定出11个不同的细胞群。与对照组相比，PPASC中髓系谱系细胞（[MLCs]；CD14⁺/CD16⁺单核细胞和树突状细胞）的比例增加。PPASC的MLCs显示出与肺部症状/纤维化相关基因的上调，而糖酵解代谢相关基因下调。同样，通路分析表明，PPASC中与纤维化相关（TGF-β、CTGF和FN1）和细胞死亡的通路上调，但免疫通路下调。在PPASC中，我们观察到MLCs之间存在相互作用的配体-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新冠病毒结局、纤维化和血管生成相关的生物学通路显著富集。进一步分析显示，与未感染新冠病毒的样本相比，PPASC中MLCs存在明显的代谢改变，糖酵解/糖异生下调。
本研究为PPASC中的免疫反应和细胞格局提供了有价值的见解。MLC水平升高及其与纤维化、免疫反应抑制和代谢状态改变相关的相应基因特征表明它们可能是PPASC的驱动因素。
