Preprint A 50-gene high-risk profile predictive of COVID & pulmonary fibrosis mortality from molecular imbalance in monocyte & T-cell subsets, 2023, Tourki +

[SNT Gatchaman]

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
Bochra Tourki; Minxue Jia; Theodoros Karampitsakos; Iset M Vera; Alyssa Arsenault; Krystin Marlin; Carole Y Perrot; Dylan Allen; Forouzandeh Farsaei; David Rutenberg; Debabrata Bandyopadhyay; Ricardo Restrepo; Muhammad R. Qureshi; Kapilkumar Patel; Argyrios Tzouvelekis; Maria Kapetanaki; Brenda Juan-Guardela; Kami Kim; Panayiotis V Benos; Jose Herazo-Maya

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.


Link | PDF (Preprint: BioRxiv)

 

[SNT Gatchaman]

They're looking at interstitial lung disease (ILD) / pulmonary fibrosis as a phenotype of long Covid (non-ME). Comparing to acute Covid, recovered convalescents and idiopathic pulmonary fibrosis (IPF). This is analogous to looking at LC as ME/CFS post SARS-2 infection vs generic ME/CFS from any cause.

 

[SNT Gatchaman]

Selected summary quotes —

In terms of cell frequencies, we noticed a significant increase in CD14+ CD163+ HLA-DR low monocytes, platelets and plasmablasts, and a decrease in naive CD4T, memory CD8T GZMB+ and dendritic cells when comparing COVID-19 versus post-COVID-19-ILD. Notably, we identified a significant increase in Hematopoietic and Progenitor Stem Cells (HSPC), dendritic cells and plasmablasts when comparing post-COVID-19-ILD with IPF patients.

Among the four conditions studied, the expression of the seven gene signature was limited to circulating monocytes and platelets (to a lesser degree) compared to other immune cell populations. All seven genes were highly expressed in all the COVID-19 patients and in one IPF patient. Out of the seven genes, three genes (MCEMP1, PLBD1 and S100A12) were expressed in monocytes in the four groups studied. In post-COVID-19-ILD samples, all seven genes had decreased expression compared to COVID-19.

Strikingly, we were able to validate the existence of three risk profiles of COVID-19 patients with increased risk of mortality and poor outcomes in a separate cohort when using the 7-gene RT-qPCR test.

Also, it is possible that patients with post-COVID-ILD who do not recover, progress or have persistently long COVID symptoms, may also have a high number of 7Gene-M-MDSCs, driving a state of persistent immune dysregulation. Several lines of evidence have shown that COVID-19 is associated with dysregulated myeloid cell compartment

Despite the reproducibility and relevance of our findings, we acknowledge the limitations of our study. First, we did not investigate the underlying mechanisms that fuel this aberrant immune response and whether immune dysregulation is a cause or effect of these diseases.

Comparison of this genomic profile through scRNA-seq in patients with COVID-19, post-COVID-19-ILD and IPF suggests an initial aberrant immune response in COVID-19 that resolves over time. This aberrant immune response is characterized by increased expression of 7Gene-M-MDSCs and decreased expression of CD4 T and CD8 T cell subsets.