Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism

Patel, Maitray A.; Knauer, Michael J.; Nicholson, Michael; Daley, Mark; Nynatten, Logan R. Van; Martin, Claudio M.; Patterson, Eric K.; Cepinskas, Gediminas; Seney, Shannon; Dobretzberger, Verena; Miholits, Markus; Webb, Brian; Fraser, Douglas D.

doi:10.1186/s10020-022-00548-8

Cited by 52 publications

(49 citation statements)

References 54 publications

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“…Similarly, coagulation and inflammation were associated with Long COVID (Nalbandian et al 2021;Pretorius, et al 2021). We previously reported significant elevations in 14 vascular transformation biomarkers, including ANGPT1 and SELP, which are also a part of the top 119 proteins in this study (Patel et al 2022). ANGPT1 has vascular protective effects while ANGPTL2 promoted angiogenesis (Thorin-Trescases and Thorin 2014; Brindle et al 2006); however, in Long-COVID subjects, the ANGPT1/ ANGPT2 ratio is dramatically increased indicating that the angiopoietin system is associated with vascular protection.…”

Section: Discussionsupporting

confidence: 63%

“…A few mechanisms have been proposed to explain the multi-system symptoms of Long-COVID including prolonged hyper-inflammation (Ortelli, et al 2021 ; Patterson et al 2021a ; Patterson et al 2021b ), autonomic nervous system disruption (Dani et al 2021 ), and persistent thrombosis (Silva Andrade et al 2021 ). We recently reported angiogenesis as a key mechanism in Long-COVID outpatients, with the elevation of 14 blood vascular transformation biomarkers (Patel et al 2022 ). Identification of accurate Long-COVID-specific biomarkers allows for early disease detection, accurate diagnosis, prognosis and/or targeted therapeutics.…”

Section: Introductionmentioning

confidence: 99%

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Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning

Patel

Knauer

Nicholson

et al. 2023

Mol Med

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Background Survivors of acute COVID-19 often suffer prolonged, diffuse symptoms post-infection, referred to as “Long-COVID”. A lack of Long-COVID biomarkers and pathophysiological mechanisms limits effective diagnosis, treatment and disease surveillance. We performed targeted proteomics and machine learning analyses to identify novel blood biomarkers of Long-COVID. Methods A case–control study comparing the expression of 2925 unique blood proteins in Long-COVID outpatients versus COVID-19 inpatients and healthy control subjects. Targeted proteomics was accomplished with proximity extension assays, and machine learning was used to identify the most important proteins for identifying Long-COVID patients. Organ system and cell type expression patterns were identified with Natural Language Processing (NLP) of the UniProt Knowledgebase. Results Machine learning analysis identified 119 relevant proteins for differentiating Long-COVID outpatients (Bonferonni corrected P < 0.01). Protein combinations were narrowed down to two optimal models, with nine and five proteins each, and with both having excellent sensitivity and specificity for Long-COVID status (AUC = 1.00, F1 = 1.00). NLP expression analysis highlighted the diffuse organ system involvement in Long-COVID, as well as the involved cell types, including leukocytes and platelets, as key components associated with Long-COVID. Conclusions Proteomic analysis of plasma from Long-COVID patients identified 119 highly relevant proteins and two optimal models with nine and five proteins, respectively. The identified proteins reflected widespread organ and cell type expression. Optimal protein models, as well as individual proteins, hold the potential for accurate diagnosis of Long-COVID and targeted therapeutics.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning

Patel

Knauer

Nicholson

et al. 2023

Mol Med

Self Cite

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“…A long-lasting reduction in vascular density, specifically affecting small capillaries, was found in patients with long COVID compared with controls, 18 months after infection 65 . A study finding elevated levels of vascular transformation blood biomarkers in long COVID also found that the angiogenesis markers ANG1 and P-selectin both had high sensitivity and specificity for predicting long COVID status 66 .…”

Section: Major Findingsmentioning

confidence: 94%

Long COVID: major findings, mechanisms and recommendations

Davis¹,

McCorkell²,

et al. 2023

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Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process.

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“…Multiple studies have investigated associations between P-selectin expression and COVID-19, including correlations with disease severity. Generally most [29][30][31][32][33][34] , but not all [35][36][37] , studies show that soluble P-selectin expression increases with disease severity, and serum P-Selectin has shown sensitivity and specificity as a biomarker for Long-COVID 38 . Moreover, a recent trial using the anti-P-Selectin antibody Crizanlizumab to treat 22 COVID-19 patients with moderate disease showed that a single injection of Crizanlizumab was safe 39 however Crizanlizumab did not alter the clinical outcomes measured (hospital discharge, or clinical status).…”

Section: Discussionmentioning

confidence: 99%

P-Selectin promotes SARS-CoV-2 interactions with platelets and the endothelium

Moreno

Castanheira

Stella

et al. 2023

Preprint

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COVID-19 causes a clinical spectrum of acute and chronic illness and host / virus interactions are not completely understood. To identify host factors that can influence SARS-CoV-2 infection, we screened the human genome for genes that, when upregulated, alter the outcome of authentic SARS-CoV-2 infection. From this, we identify 34 new genes that can alter the course of infection, including the innate immune receptor P-selectin, which we show is a novel SARS-CoV-2 spike receptor. At the cellular level expression of P-selectin does not confer tropism for SARS-CoV-2, instead it acts to suppress infection. More broadly, P-selectin can also promote binding to SARS-CoV-2 variants, SARS-CoV-1 and MERS, acting as a general spike receptor for highly pathogenic coronaviruses. P-selectin is expressed on platelets and endothelium, and we confirm SARS-CoV-2 spike interactions with these cells are P-selectin-dependent and can occur under shear flow conditions. In vivo, authentic SARS-CoV-2 uses P-selectin to home to airway capillary beds where the virus interacts with the endothelium and platelets, and blocking this interaction can clear vascular-associated SARS-CoV-2 from the lung. Together we show for the first time that coronaviruses can use the leukocyte recruitment system to control tissue localization, and this fundamental insight may help us understand and control highly pathogenic coronavirus disease progression.

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Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism

Cited by 52 publications

References 54 publications

Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning

Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning

Long COVID: major findings, mechanisms and recommendations

P-Selectin promotes SARS-CoV-2 interactions with platelets and the endothelium

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