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BALF gene expression profiling reveals innate immune activation bias in persistent post-COVID-19 ILD

ABSTRACT: Survivors of COVID-19 can experience long-term lung complications (pulmonary sequelae), but the underlying mechanisms remain unclear. While most patients with major COVID-19 lung injury eventually recover essentially completely, some experience significant residual damage. To investigate the underlying differences, we analyzed, using bronchoalveolar lavage fluid (BALF), the alveolar immune cell compartments of a group of patients with post-COVID-19 interstitial lung disease (ILD) six months after acute COVID-19. Patients were categorized into two groups, based on High-Resolution Computed Tomography (HRCT) evaluation a year later: those with persistent HRCT abnormalities compatible with fibrosis (persistent post-COVID-19 ILD, n=6) and those with resolved lung lesions (resolved post-COVID-19 ILD, n=13). Additionally, 6 patients with pre-existing ILD were included in the study, after recovery from COVID-19. Bulk RNA transcriptomics analyses of BALF cells revealed pathways of neutrophil and monocyte chemotaxis to be enriched in patients with persistent HRCT abnormalities, consistent with increased monocyte-like cell recruitment in the lungs. Furthermore, increased gene expression of markers of pro-fibrotic macrophages/monocytes, such as SPP1 and pro-inflammatory cytokines, such as Il-1b, was also observed. Conversely, patients with resolved post-COVID-19 ILD displayed BALF cell gene expression signatures indicative of T-cell activation. Additionally, BALF gene expression patterns associated with pro-fibrotic macrophage activation, neutrophil chemotaxis and downregulation of T-cell activation were also observed in patients with pre-existing fibrotic ILD following COVID-19. These findings suggest that immune response imbalance leading to prolonged activation of innate immunity and subdued adaptive immune responses may be associated with persistent post-COVID-19 ILD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291409 | GEO | 2026/02/25

REPOSITORIES: GEO

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Project description:Background: We previously identified a 50-gene signature that distinguished two groups of patients with increased risk of COVID-19 and IPF mortality. In this study we aimed to validate our previous findings and to study the source and trajectory of circulating immune cells expressing these 50 genes in patients with COVID19, post-COVID-19 Interstitial Lung Disease (ILD) and Idiopathic Pulmonary Fibrosis (IPF). Methods: Whole blood and Peripheral Blood Mononuclear cells (PBMC) were obtained from 216 hospitalized patients with COVID-19, five patients with post-COVID-19-ILD, six patients with IPF and four controls from the University of South Florida (USF)/Tampa General Hospital (TGH). We measured the expression of the 50-gene signature using the nCounter analysis system (Nanostring), and the levels of Interleukin 6 (IL6), interferon γ-induced protein (IP10), Secreted Phosphoprotein 1 (SPP1) and transforming growth factor beta (TGF-β) in these patients by Luminex and Elisa tests. A 7-gene PCR assay was generated to validate the identification of COVID-19 endotypes. For single-cell RNA sequencing (scRNA-seq) we used Chromium Single Cell Controller (10X Genomics). For analysis of gene expression, we used the Scoring Algorithm of Molecular Subphenotypes (SAMS), Cell Ranger and Seurat packages. For statistical analysis, we used Kaplan-Meier survival curves, CoxPH models, Two-way ANOVA, T-test, Fisher’s exact and the Wilcoxon rank test. Results: We identified the presence of three genomic risk profiles based on the 50-gene signature, and a subset of seven genes, associated with low, intermediate, or high-risk of mortality in COVID-19. These risk groups had significant differences in IL6, IP10, SPP1 and TGFβ-1 levels. By applying scRNA-seq, we discovered a novel subtype of Monocytic-Myeloid-Derived Suppressive cells (M-MDSCs) expressing CD14+HLA DRlowCD163+ and high levels of the 7-gene signature. We denominated these cells as 7Gene-M-MDSC. These cells were not observed in survivors with post-COVID-19-ILD. The 43-gene signature was mostly expressed in naive CD4 T and memory CD4 T cells, Tregs, memory CD8 T GZMB+, memory CD8 T GZMK+ and naive CD8 T cells. While increased expression of genes in the 43 gene signature was seen in T cell subsets from survivors with post-COVID-19 ILD, the expression of these genes remained low in IPF. Conclusion: A 50-gene, high-risk genomic profile in peripheral blood of COVID-19 can accurately predict COVID-19 mortality. This profile is characterized by a simultaneous increase in expression of seven genes originating from 7Gene-M-MDSCs and decreased expression of 43 genes originating primarily in T cell subsets. While increased expression of these 43 genes can be seen in survivors with post-COVID-19 ILD, their expression remains low in IPF.

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BALF gene expression profiling reveals innate immune activation bias in persistent post-COVID-19 ILD

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