Plasma proteome of Long-COVID patients indicates HIF-mediated vasculo-proliferative disease with impact on brain and heart function

Abstract

Aims Long-COVID occurs after SARS-CoV-2 infection and results in diverse, prolonged symptoms. The present study aimed to unveil potential mechanisms, and to inform prognosis and treatment. Methods Plasma proteome from Long-COVID outpatients was analyzed in comparison to matched acutely ill COVID-19 (mild and severe) inpatients and healthy control subjects. The expression of 3072 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 cell redistribution with a dominant resting phenotype, as opposed to active, and neutrophils that formed extracellular traps. This potential resetting of cell phenotypes was reflected in prospective vascular events mediated by both angiopoietin-1 (ANGPT1) and vascular-endothelial growth factor-A (VEGFA). Several markers (ANGPT1, VEGFA, CCR7, CD56, citrullinated histone 3, elastase) were validated by serological methods in additional patient cohorts. Signaling of transforming growth factor-β1 with probable connections to elevated EP/p300 suggested vascular inflammation and tumor necrosis factor-α driven pathways. In addition, a vascular proliferative state associated with hypoxia inducible factor 1 pathway suggested progression from acute COVID-19 to Long-COVID. The vasculo-proliferative process predicted in Long-COVID might contribute to changes in the organ-specific proteome reflective of neurologic and cardiometabolic dysfunction. Conclusions Taken together, our findings point to a vasculo-proliferative process in Long-COVID that is likely initiated either prior hypoxia (localized or systemic) and/or stimulatory factors (i.e., cytokines, chemokines, growth factors, angiotensin, etc). Analyses of the plasma proteome, used as a surrogate for cellular signaling, unveiled potential organ-specific prognostic biomarkers and therapeutic targets.

Restrained memory CD8+T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID

“…Reports of innate cell perturbations in patients with Long COVID have been published but results are variable and somewhat conflicting 55 . We find monocyte redistribution in favor of CD33-expressing classical monocytes in Long COVID and elevated plasma proteins such as TNFα and TRAIL suggesting ongoing monocyte activation, in line with previous findings 56,57 . Another recent paper reported a dysregulated activation of the complement system, which could be linked to antibody-responses, either to SARS-CoV-2 or to reactivated herpesviruses 58 .…”

Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome

“…Indeed, recent studies have suggested that patients with LC may suffer from chronic hypoxic changes affecting the brain ( 21 ). Consistent with this, a vascular inflammation associated with hypoxia-inducible factor-1 is reported to contribute to neurological and cardiometabolic dysfunction in LC ( 22 ).…”

The plasma proteome differentiates the multisystem inflammatory syndrome in children (MIS-C) from children with SARS-CoV-2 negative sepsis

“…ANGPT1 is increased in the MIS-C cohort and is angiogenic with vascular protective effects [ 99 ]. As a primary regulator of angiogenesis, ANGPT1 is highly elevated in Long-COVID patients [ 27 , 30 , 100 ]. PPBP, also known as CXCL7, is elevated in the MIS-C cohort.…”

“…Thus, the primary goal of this study was to identify blood proteins specific to MIS-C inpatients relative to age- and sex-matched SCNS patients. Our specific objectives were: (1) to measure a large number of blood proteins from each cohort with targeted proteomics [ 25 – 30 ]; (2) to determine the relative importance of the proteins with machine learning to differentiate MIS-C subjects; (3) to correlate protein expression with clinically relevant MIS-C variables; and (4) to determine the cell types and organ systems in which the important proteins are expressed.…”