A 50-gene high-risk profile predictive of COVID-19 and Idiopathic Pulmonary Fibrosis mortality originates from a genomic imbalance in monocyte and T-cell subsets that reverses in survivors with post-COVID-19 Interstitial Lung Disease

Abstract

Background: We aim to study the source of circulating immune cells expressing a 50-gene signature predictive of COVID-19 and IPF mortality. Methods: Whole blood and Peripheral Blood Mononuclear cells (PBMC) were obtained from 231 subjects with COVID-19, post-COVID-19-ILD, IPF and controls. We measured the 50-gene signature (nCounter, Nanostring), interleukin 6 (IL6), interferon gamma;-induced protein (IP10), secreted phosphoprotein 1 (SPP1) and transforming growth factor beta (TGF-beta) by Luminex. PCR was used to validate COVID-19 endotypes. For single-cell RNA sequencing (scRNA-seq) we used Chromium Controller (10X Genomics). For analysis we used the Scoring Algorithm of Molecular Subphenotypes (SAMS), Cell Ranger, Seurat, Propeller, Kaplan-Meier curves, CoxPH models, Two-way ANOVA, T-test, and Fisher exact. Results: We identified 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 with significant differences in IL6, IP10, SPP1 and TGFβ-1. scRNA-seq identified Monocytic-Myeloid-Derived Suppressive cells (M-MDSCs) expressing CD14+HLA DRlowCD163+ and high levels of the 7-gene signature (7Gene-M-MDSC) in COVID-19. These cells were not observed in post-COVID-19-ILD or IPF. The 43-gene signature was mostly expressed in CD4 T and CD8 T cell subsets. Increased expression of 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 profile in COVID-19 is characterized by a genomic imbalance in monocyte and T-cell subsets that reverses in survivors with post-COVID-19 Interstitial Lung Disease.

Risk of newly diagnosed interstitial lung disease after COVID-19 and impact of vaccination: a nationwide population-based cohort study

“…Peripheral blood mononuclear cell signatures in COVID-19 lung disease and IPF have also been shown to exhibit comparable transcriptional signatures and have prognostic value ( 42 ). There is also evidence that monocyte and T cell subsets are involved in the pathogenesis of post-COVID-19 ILD; a recent study evaluating blood samples from subjects with post-COVID-19 ILD, IPF, and controls showed that survivors of post-COVID-19 ILD had higher expression of genes related to naïve and memory CD4 T cells, Tregs, memory CD8 T GZMB+, memory CD8 T GZMK+, and naïve CD8 T cells, but lower levels in IPF, suggesting most subjects with post-COVID-19 ILD have partially or completely resolved pulmonary fibrosis, while most patients with IPF have progressive disease ( 43 ). Further studies are still needed to determine the exact mechanism(s) underlying ILD after COVID-19, but the results of previous studies suggest that the complex immune response to the virus itself may promote the development of ILD after COVID-19.…”