Longitudinal proteomic profiling of dialysis patients with COVID-19 reveals markers of severity and predictors of death

Gisby, Jack; Clarke, Candice; Medjeral-Thomas, Nicholas; Malik, Talat H.; Papadaki, Artemis; Mortimer, Paige M; Buang, Norzawani; Lewis, Shanice; Pereira, Marie; Toulza, Frédéric; Fagnano, Ester; Mawhin, Marie‐Anne; Dutton, Emma E; Tapeng, Lunnathaya; Richard, Alison F.; Kirk, Paul D. W.; Behmoaras, Jacques; Sandhu, Eleanor; McAdoo, Stephen P; Prendecki, Maria; Pickering, Matthew C.; Botto, Marina; Willicombe, Michelle; Thomas, David C.; Peters, James E.

doi:10.7554/elife.64827

Cited by 63 publications

(73 citation statements)

References 61 publications

(74 reference statements)

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“…These data suggest that genetic propensity to higher soluble FAS levels influences COVID-19 severity, but not susceptibility. Observational data from the analysis of Gisby et al 11 revealed a similar pattern. Plasma FAS was not significantly differentially abundant in the comparison of all COVID-19 cases versus uninfected controls (Benjamini-Hochberg adjusted P value 0.280), but it was highly significantly associated with COVID-19 severity grading within-cases (Benjamini-Hochberg adjusted P 0.019) (Fig.…”

Section: Resultsmentioning

confidence: 69%

“…We first identified a list of proteins associated with COVID-19 clinical severity grading by examining two studies that performed broad proteomic profiling of COVID-19 patient plasma samples using the Olink proteomics platform 10,11 . We took the lists of severity-associated proteins from each study (Benjamini-Hochberg adjusted P <0.05) and intersected these to provide a highconfidence list of 157 severity-associated proteins (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…A wide range of therapies directed at specific elements of the inflammatory response have been developed for autoimmune and inflammatory diseases 8,9 , and present potential repurposing opportunities for treatment of COVID-19. Profiling of plasma proteins in COVID-19 patients has revealed a signature of innate immune cell activation (including upregulation of IL-6, monocyte chemokines and neutrophil proteins) and epithelial/endothelial injury in severe disease 10,11 . A limitation of such observational studies, however, is that they cannot distinguish causal mediators of immunopathology from secondary downstream consequences of inflammation and/or tissue injury.…”

Section: Mainmentioning

confidence: 99%

“…We identified plasma proteins that were significantly associated (5% FDR) with COVID-19 severity in the two studies that used Olink proteomics platform (Filbin et al 10 and Gisby et al 11 ).…”

Section: Defining a List Of Proteins Robustly Associated With Covid-19 Severitymentioning

confidence: 99%

“…We used data on COVID-19 patients and sex, age and ethnicity matched non-infected controls from the study by Gisby et al 11 . The study design involved serial plasma sampling from the COVID-19 patients.…”

Section: Fas Levels In Covid-19 Patientsmentioning

confidence: 99%

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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19

Klarić¹,

Gisby²,

Papadaki³

et al. 2021

Preprint

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Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.

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Section: Resultsmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

Section: Defining a List Of Proteins Robustly Associated With Covid-19 Severitymentioning

confidence: 99%

Section: Fas Levels In Covid-19 Patientsmentioning

confidence: 99%

See 3 more Smart Citations

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19

Klarić¹,

Gisby²,

Papadaki³

et al. 2021

Preprint

Self Cite

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Combination of WFDC2, CHI3L1, and KRT19 in Plasma Defines a Clinically Useful Molecular Phenotype Associated with Prognosis in Critically Ill COVID-19 Patients

et al. 2022

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Background COVID-19 is now a common disease, but its pathogenesis remains unknown. Blood circulating proteins reflect host defenses against COVID-19. We investigated whether evaluation of longitudinal blood proteomics for COVID-19 and merging with clinical information would allow elucidation of its pathogenesis and develop a useful clinical phenotype. Methods To achieve the first goal (determining key proteins), we derived plasma proteins related to disease severity by using a first discovery cohort. We then assessed the association of the derived proteins with clinical outcome in a second discovery cohort. Finally, the candidates were validated by enzyme-linked immunosorbent assay in a validation cohort to determine key proteins. For the second goal (understanding the associations of the clinical phenotypes with 28-day mortality and clinical outcome), we assessed the associations between clinical phenotypes derived by latent cluster analysis with the key proteins and 28-day mortality and clinical outcome. Results We identified four key proteins (WFDC2, GDF15, CHI3L1, and KRT19) involved in critical pathogenesis from the three different cohorts. These key proteins were related to the function of cell adhesion and not immune response. Considering the multicollinearity, three clinical phenotypes based on WFDC2, CHI3L1, and KRT19 were identified that were associated with mortality and clinical outcome. Conclusion The use of these easily measured key proteins offered new insight into the pathogenesis of COVID-19 and could be useful in a potential clinical application.

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SARS-CoV-2 infection in dialysis and kidney transplant patients: immunological and serological response

et al. 2022

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Background Dialysis and kidney transplant patients with moderate-severe COVID-19 have a high mortality rate, around 30%, that is similar in the two populations, despite differences in their baseline characteristics. In these groups, the immunology of the disease has been poorly explored. Methods Thirty-two patients on dialysis or with kidney transplant and SARS-CoV-2 infection requiring hospitalization (COV group) were included in our study. Lymphocyte subsets, dendritic cell (DC) counts and monocyte activation were studied. SARS-CoV-2 anti-spike/anti-nucleocapsid were monitored, and baseline cytokines and chemokines were measured in 10 patients. Results The COV group, compared to healthy subjects and uninfected dialysis/kidney transplant controls, showed lower numbers of CD4 + and CD8 + T cells, Natural-Killer (NK), B cells, plasmacytoid and myeloid DCs, while the proportion of terminally differentiated B-cells was increased. IL6, IL10, IFN-α and chemokines involved in monocyte and neutrophil recruitment were higher in the COV group, compared to uninfected dialysis/kidney transplant controls. Patients with severe disease had lower CD4 + , CD8 + and B-cell counts and lower monocyte HLA-DR expression. Of note, when comparing dialysis and kidney transplant patients with COVID-19, the latter group presented lower NK and pDC counts and monocyte HLA-DR expression. Up to 60 days after symptom onset, kidney transplant recipients showed lower levels of anti-spike antibodies compared to dialysis patients. Conclusions During SARS-CoV-2 infection, dialysis and kidney transplant patients manifest immunophenotype abnormalities; these are similar in the two groups, however kidney transplant recipients show more profound alterations of the innate immune system and lower anti-spike antibody response. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s40620-021-01214-8.

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Longitudinal proteomic profiling of dialysis patients with COVID-19 reveals markers of severity and predictors of death

Cited by 63 publications

References 61 publications

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19

Combination of WFDC2, CHI3L1, and KRT19 in Plasma Defines a Clinically Useful Molecular Phenotype Associated with Prognosis in Critically Ill COVID-19 Patients

SARS-CoV-2 infection in dialysis and kidney transplant patients: immunological and serological response

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