Plasma proteome of Long-COVID patients indicates HIF-mediated vasculo-proliferative disease with impact on brain and heart function, 2023, Iosef et al

Plasma proteome of Long-COVID patients indicates HIF-mediated vasculo-proliferative disease with impact on brain and heart function
Iosef, Cristiana; Knauer, Michael J.; Nicholson, Michael; Van Nynatten, Logan R.; Cepinskas, Gediminas; Draghici, Sorin; Han, Victor K. M.; Fraser, Douglas D.

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 ageand 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.

Link | PDF (Journal of Translational Medicine)

 

Same group as —

Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning (2023)
Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism (2022)

We wanted an infected recovered group in the 2023 study but it looks as if this one has the same deficiency.

 

The results section has subsections titled —

• Natural killer (NK) cells of Long‑COVID outpatients changed phenotype from activated to resting
• Immune cell resetting is potentially associated with vascular events mediated by VEGFA
• Plasma proteome analysis suggested “Neutrophil Extracellular Trap formation”
• EP/p300 could potentially favor vascular inflammation via TNF signaling
• HIF signaling pattern reflected in the plasma proteome could be related to vascular proliferation
• Plasma proteome of Long‑COVID reflects cell proliferation patterns
• Long‑COVID associated brain dysfunction reflected in the plasma proteome
• Long‑COVID associated cardiometabolic dysfunction reflected in the plasma proteome

 

It seems like Douglas Fraser et al. always choose the same group of patients that don't seem to represent the "classical" Long-Covid patients (predominantly female and younger patients), but rather those that seem to suffer from acute Covid more (predominantly older, a slight majority of males, often with pre-existing conditions) with predominantly respiratory and coughing problems in Long-Covid, both of which seem to be rather self-resolving. I'm also not able to see whether these people are smokers, as coughing or respiratory problems wouldn't really surprise me in a 70 year old smoker with asthma. The question is how these findings would translate to a 30 year old female with brain fog and PEM and whether the disease progression would be the same in this group of patients.