ABSTRACT
Aims Long-COVID occurs after SARS-CoV-2 infection and results in diverse, prolonged symptoms. The present study aims to determine the underlying mechanisms, and to inform prognosis and treatment.Methods Plasma proteome from Long-COVID outpatients was analyzed in comparison to acutely ill COVID-19 (mild and severe) inpatients and healthy control subjects. The expression of approximately 3000 protein biomarkers was determined with proximity extension assays and then deconvoluted with multiple bioinformatics tools into both cell types and signaling mechanisms, as well as organ specificity.Results Compared to age- and sex-matched acutely ill COVID-19 inpatients and healthy control subjects, Long-COVID outpatients showed natural killer cells with a resting phenotype, as opposed to active, and neutrophils that formed extracellular traps. This resetting of cell phenotypes was reflected in vascular events mediated by both angiopoietin-1 (ANGPT1) and vascular-endothelial growth factor-A (VEGFA). Levels of ANGPT1 and VEGFA were validated by serological methods in different patient cohorts. Silent signaling of transforming growth factor-β1 with elevated EP300 favored not only vascular inflammation, but also tumor necrosis factor-α driven pathways. In addition, a vascular proliferative state associated with hypoxia inducible factor 1 pathway was predicted that progressed from COVID-19 to Long-COVID. The vasculo-proliferative process identified in Long-COVID was associated with significant changes in the organ-specific proteome reflective of neurological and cardiometabolic dysfunction.Conclusions Taken together, our study uncovered a vasculo-proliferative process in Long-COVID initiated by prior hypoxia, and identified potential organ-specific prognostic biomarkers and therapeutic targets.
Subject(s)
Necrosis , Neoplasms , Hypoxia , Nervous System Diseases , COVID-19 , InflammationABSTRACT
Background: COVID19 is caused by the SARS-CoV-2 virus and has been associated with severe inflammation leading to organ dysfunction and mortality. Our aim was to profile the transcriptome in leukocytes from critically ill patients positive for COVID19 compared to those negative for COVID19 to better understand the COVID19 associated host response. For these studies, all patients admitted to our tertiary care intensive care unit (ICU) suspected of being infected with SARS-CoV-2, using standardized hospital screening methodologies, had blood samples collected at the time of admission to the ICU. Transcriptome profiling of leukocytes via ribonucleic acid sequencing (RNAseq) was then performed and differentially expressed genes as well as significantly enriched gene sets were identified. Results: : We enrolled seven COVID19+ (PCR positive, 2 SARS-CoV-2 genes) and seven age- and sex-matched COVID19- (PCR negative) control ICU patients. Cohorts were well-balanced with the exception that COVID19- patients had significantly higher total white blood cell counts and circulating neutrophils and COVID19+ patients were more likely to suffer bilateral pneumonia. The mortality rate for this cohort of COVID19+ ICU patients was 29%. As indicated by both single-gene based and gene set (GSEA) approaches, the major disease-specific transcriptional responses of leukocytes in critically ill COVID19+ ICU patients were: (i) a robust overrepresentation of interferon related gene expression; (ii) a marked decrease in the transcriptional level of genes contributing to general protein synthesis and bioenergy metabolism; and (iii) the dysregulated expression of genes associated with coagulation, platelet function, complement activation, and tumour necrosis factor/interleukin 6 signalling. Conclusions: : Our findings demonstrate that critically ill COVID19+ patients on day 1 of admission to the ICU display a unique leukocyte transcriptional profile that distinguishes them from COVID19- patients, providing guidance for future targeted studies exploring novel prognostic and therapeutic aspects of COVID19.