Tourki Bochra, Jia Minxue, Karampitsakos Theodoros, Vera Iset M, Arsenault Alyssa, Fatima Zainab, Perrot Carole Y, Allen Dylan, Farsaei Forouzandeh, Rutenberg David, Bandyopadhyay Debabrata, Restrepo-Jaramillo Ricardo, Qureshi Muhammad R, Patel Kapilkumar, Tzouvelekis Argyris, Kapetanaki Maria G, Juan-Guardela Brenda M, Kim Kami, Benos Panayiotis V, Herazo-Maya Jose D
Ubben Center for Pulmonary Fibrosis Research, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States.
Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
Am J Physiol Cell Physiol. 2025 Jan 1;328(1):C199-C211. doi: 10.1152/ajpcell.00528.2024. Epub 2024 Nov 7.
We aimed to study transcriptional and phenotypic changes in circulating immune cells associated with increased risk of mortality in COVID-19, resolution of pulmonary fibrosis in post-COVID-19-interstitial lung disease (ILD), and persistence of idiopathic pulmonary fibrosis (IPF). Whole blood and peripheral blood mononuclear cells (PBMCs) were obtained from 227 subjects with COVID-19, post-COVID-19 interstitial lung disease (ILD), IPF, and controls. We measured a 50-gene signature (nCounter, Nanostring) previously found to be predictive of IPF and COVID-19 mortality along with plasma levels of several biomarkers by Luminex. In addition, we performed single-cell RNA sequencing (scRNA-seq) in PBMCs (10x Genomics) to determine the cellular source of the 50-gene signature. We identified the presence of three genomic risk profiles in COVID-19 based on the 50-gene signature associated with low-, intermediate-, or high-risk of mortality and with significant differences in proinflammatory and profibrotic cytokines. Patients with COVID-19 in the high-risk group had increased expression of seven genes in CD14HLA-DRCD163 monocytic-myeloid-derived suppressive cells (7Gene-M-MDSCs) and decreased expression of 43 genes in CD4 and CD8 T cell subsets. The loss of 7Gene-M-MDSCs and increased expression of these 43 genes in T cells was seen in survivors with post-COVID-19-ILD. On the contrary, patients with IPF had low expression of the 43 genes in CD4 and CD8 T cells. Collectively, we showed that a 50-gene, high-risk profile, predictive of IPF and COVID-19 mortality is characterized by a genomic imbalance in monocyte and T-cell subsets. This imbalance reverses in survivors with post-COVID-19-ILD highlighting genomic differences between post-COVID-19-ILD and IPF. Changes in the 50-gene signature, reflective of increase in CD14HLA-DRCD163 monocytes and decrease in CD4 and CD8 T cells, are associated with increased mortality in COVID-19. A reversal of this pattern can be seen in post-COVID-19-ILD, whereas its persistence can be seen in IPF. Modulating the imbalance between HLA-DR monocytes and T cell subsets should be investigated as a potential strategy to treat pulmonary fibrosis associated with severe COVID-19 and progressive IPF.
我们旨在研究与新冠病毒疾病（COVID-19）死亡风险增加、新冠后间质性肺病（ILD）肺纤维化的消退以及特发性肺纤维化（IPF）的持续存在相关的循环免疫细胞中的转录和表型变化。从227名患有COVID-19、新冠后间质性肺病（ILD）、IPF的受试者以及对照组中获取全血和外周血单个核细胞（PBMC）。我们检测了先前发现可预测IPF和COVID-19死亡率的50基因特征（nCounter，Nanostring）以及通过Luminex检测的几种生物标志物的血浆水平。此外，我们对PBMC进行了单细胞RNA测序（scRNA-seq，10x Genomics）以确定50基因特征的细胞来源。基于与低、中、高死亡风险相关且促炎和促纤维化细胞因子存在显著差异的50基因特征，我们在COVID-19中鉴定出三种基因组风险概况。高风险组的COVID-19患者在CD14⁺HLA-DR⁺CD163⁺单核细胞 - 骨髓来源的抑制性细胞（7基因 - M - MDSCs）中有七个基因表达增加，而在CD4和CD8 T细胞亚群中有43个基因表达减少。在新冠后ILD幸存者中可见7基因 - M - MDSCs的减少以及T细胞中这43个基因表达的增加。相反，IPF患者在CD4和CD8 T细胞中这43个基因表达较低。总体而言，我们表明，一个可预测IPF和COVID-19死亡率的50基因高风险概况的特征是单核细胞和T细胞亚群中的基因组失衡。这种失衡在新冠后ILD幸存者中会逆转，突出了新冠后ILD和IPF之间的基因组差异。反映CD14⁺HLA-DR⁺CD163⁺单核细胞增加和CD4及CD8 T细胞减少的50基因特征变化与COVID-19死亡率增加相关。在新冠后ILD中可看到这种模式的逆转，而在IPF中可看到其持续存在。调节HLA - DR单核细胞和T细胞亚群之间的失衡应作为治疗与重症COVID-19和进行性IPF相关的肺纤维化的潜在策略进行研究。
