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

Tourki, B.; Jia, M.; Karampitsakos, T.; Vera, I. M.; Arsenault, A.; Marlin, K.; Perrot, C. Y.; Allen, D.; Farsaei, F.; Rutenberg, D.; Bandyopadhyay, D.; Restrepo, R.; Qureshi, M. R.; Patel, K.; Tzouvelekis, A.; Kapetanaki, M.; Juan-Guardela, B.; Kim, K.; Benos, P. V.; Herazo-Maya, J.

doi:10.1101/2023.10.22.563156

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bioRxiv · 10.1101/2023.10.22.563156

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

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Abstract

BackgroundWe aim to study the source of circulating immune cells expressing a 50-gene signature predictive of COVID-19 and IPF mortality. MethodsWhole 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 Fishers exact. ResultsWe 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 TGF{beta}-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. ConclusionA 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

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Tourki, B., Jia, M., Karampitsakos, T., Vera, I. M., Arsenault, A., Marlin, K., Perrot, C. Y., Allen, D., Farsaei, F., Rutenberg, D., Bandyopadhyay, D., Restrepo, R., Qureshi, M. R., Patel, K., Tzouvelekis, A., Kapetanaki, M., Juan-Guardela, B., Kim, K., Benos, P. V., Herazo-Maya, J.. 2023-10-24. A 50-gene high-risk profile predictive of COVID-19 and Idiopathic Pulmonary Fibrosis mortality originates from a molecular imbalance in monocyte and T-cell subsets that reverses in survivors with post-COVID-19 Interstitial Lung Disease. https://doi.org/10.1101/2023.10.22.563156

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