Untargeted metabolomics of serum samples during COVID-19 disease progression
Lead Research Organisation:
University of Liverpool
Department Name: Biochemistry
Abstract
Understanding changes in the biochemistry of an individual who is ostensibly healthy, including when they may show no overt symptoms of infection with SARS-Cov2, remains a huge challenge. Similar questions apply to understanding who is likely to live (unaided or via intervention) and who will die from COVID-19 once diagnosed, and the answers are equally unknown. Since we do not presently have any knowledge (although we know that there are cardiovascular changes that should have easily measured metabolic consequences (Zheng YY, Ma YT, Zhang JY, Xie X: COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020), the best approach is to measure everything and find out.
This approach is known as 'untargeted metabolomics'. We are experts in it (Kell co-invented the term 'metabolome'), and have already discovered novel measures of cardiovascular stress. We now wish to apply these to cohorts of serum samples that are already being collected in Liverpool and which will be made available to us (after treatment to remove all proteins, including virus). We anticipate that we shall be able to find markers that could be very early predictors of COVID-19 infection and prognosis.
This approach is known as 'untargeted metabolomics'. We are experts in it (Kell co-invented the term 'metabolome'), and have already discovered novel measures of cardiovascular stress. We now wish to apply these to cohorts of serum samples that are already being collected in Liverpool and which will be made available to us (after treatment to remove all proteins, including virus). We anticipate that we shall be able to find markers that could be very early predictors of COVID-19 infection and prognosis.
Publications
Roberts I
(2023)
Quantitative LC-MS study of compounds found predictive of COVID-19 severity and outcome.
in Metabolomics : Official journal of the Metabolomic Society
Roberts I
(2021)
Untargeted metabolomics of COVID-19 patient serum reveals potential prognostic markers of both severity and outcome
in Metabolomics
| Description | We have here performed a well-powered, untargeted metabolomics analysis of serum of COVID-19 patients with the aim of finding prognostic markers of disease severity and outcome. Using both univariate and a multiple predictor Bayesian logistic regression model we found a subset of 20 metabolites with relevant biological functions that are predictive of subsequent disease severity and patient outcome. Although, no individual metabolite appeared be strongly discriminative on its own, a combined model based on viral activity, host immune response and underlying metabolic differences showed promising predictive results with AUC 0.792 and 0.793, respectively. |
| Exploitation Route | The markers identified hold promise to improve patient care upon COVID-19 infection and diagnosis. Building on these encouraging results, further work will aim to validate those findings and their prognostic potential in a longitudinal study. |
| Sectors | Healthcare |
| Description | Stellenbosch |
| Organisation | University of Stellenbosch |
| Country | South Africa |
| Sector | Academic/University |
| PI Contribution | Extraordinary (Honorary) Professor , Department of Physiological Science, Stellenbosch University Collaborative research in the areas of anti-microbial resistance, membrane transporters, dormant microbes as elements of supposedly non-communicable diseases, iron dysregulation, and enzyme improvement. |
| Collaborator Contribution | Sharing of knowledge and analytical facilities at Stellenbosch, Manchester and Liverpool. |
| Impact | Press release: Research opens door into new treatment options for chronic inflammatory diseases http://www.sun.ac.za/english/Lists/news/DispForm.aspx?ID=5104 Bezuidenhout J, Venter C, Roberts T, Tarr G, Kell D, Pretorius E (2020. Detection of citrullinated fibrin in plasma clots of RA patients and its relation to altered structural clot properties, disease-related inflammation and prothrombotic tendency. Front Immunol 11, 577523. DOI 10.3389/fimmu.2020.577523. bioRxiv link. DOI:10.1101/2020.05.28.121301. Venter C, Bezuidenhout JA, Laubscher GJ, Lourens PJ, Steenkamp J, Kell DB, Pretorius E (2020). Erythrocyte, platelet, serum ferritin and P-selectin pathophysiology implicated in severe hypercoagulation and vascular complications in COVID-19. Int J Mol Sci 21, 8234. DOI: 10.3390/ijms21218234 Pretorius E, Venter C, Laubscher GJ, Lourens PJ, Steenkamp J, Kell DB (2020) Prevalence of readily detected amyloid blood clots in 'unclotted' Type 2 Diabetes Mellitus and COVID-19 plasma: A preliminary report. Cardiovasc Diabetol 19, 193. DOI 10.1186/s12933-020-01165-7. Prevalence of amyloid blood clots in COVID-19 plasma. medRxiv 2020.2007.2028.20163543v20163541. DOI 10.1101/2020.07.28.20163543. Grobler C, Maphumulo SC, Grobbelaar LM, Bredenkamp J, Laubscher J, Lourens PJ, Steenkamp J, Kell DB, Pretorius E. (2020). COVID-19: The Rollercoaster of Fibrin(ogen), D-dimer, von Willebrand Factor, P-selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes. Int J Mol Sci 21:5168. DOI: 10.3390/ijms21145168. Preprint at Grobler C, Bredenkamp J, Grobbelaar M, Maphumulo S, Laubscher J, Steenkamp J, Kell DB, Pretorius E (2020): COVID-19: The Rollercoaster of Fibrin(ogen), D-dimer, von Willebrand Factor, P-selectin and their interactions with endothelial cells, platelets and erythrocytes. Preprints.org 2020:202007.200142/v202001. Nunes JM, Fillis T, Page MJ, Venter C, Lancry O, Kell DB, Windberger U, Pretorius E (2020) Gingipain R1 and lipopolysaccharide from Porphyromonas gingivalis have major effects on blood clot morphology and mechanics. Front Immunol. 11, 1551. DOI: 10.3389/fimmu.2020.01551 Olsen I, Kell DB, Pretorius E (2020). Is Porphyromonas gingivalis involved in Parkinson's disease? Eur J Clin Microbiol Infect Dis, https://doi.org/10.1007/s10096-020-03944-2. DOI: 10.1007/s10096-020-03944-2. Kell DB, Heyden EL Pretorius, E. (2020) The biology of lactoferrin, an iron-binding protein that can help defend against viruses and bacteria. FrontiersIn Immunol 11, 1221. DOI: 10.3389/fimmu.2020.01221. Borodina I, Kenny LC, McCarthy CM, Paramasivan K, Pretorius R, Roberts TJ, van der Hoek SA, Kell DB (2020). The biology of ergothioneine, an antioxidant nutraceutical. Nutr Res Rev. 33, 190-217. Pubmed 32051057. DOI: 10.1017/S0954422419000301 de Villiers S, Bester J, Kell DB, Pretorius E (2019) Erythrocyte health and the possible role of amyloidogenic blood clotting in the evolving haemodynamics of female migraine-with-aura pathophysiology: Results from a pilot study. Frontiers Neurol 10, 1262. de Villiers S, Bester J, Kell DB, Pretorius E: Erythrocyte health and the possible role of amyloidogenic blood clotting in the evolving haemodynamics of female migraine-with-aura pathophysiology: Results from a pilot study. Cephalalgia 2019; 39:150-151 Adams B, Nunes JM, Page MJ, Roberts T, Carr J, Nell TA, Kell DB, Pretorius E (2019) Parkinson's disease: a systemic inflammatory disease accompanied by bacterial inflammagens. Front Aging Neurosci 11, 210. Preprint: bioRxiv 2019:646307v646301. DOI: 10.3389/fnagi.2019.00210 Visser MJE, Kell DB, Pretorius E (2019): Bacterial dysbiosis and translocation in psoriasis vulgaris. Front Cell Infect Microbiol 7, 9. DOI: doi: 10.3389/fcimb.2019.00007 Pretorius L, Kell DB, Pretorius E. (2018). Iron dysregulation and dormant microbes as causative agents for impaired blood rheology and pathological clotting in Alzheimer's type dementia. Frontiers in Neurosci 12, 851. DOI: 10.3389/fnins.2018.00851 de Waal GM, Engelbrecht L, Davis T, de Villiers WJS, Kell DB, Pretorius E (2018) Correlative Light-Electron Microscopy detects lipopolysaccharide and its association with fibrin fibres in Parkinson's Disease, Alzheimer's Disease and Type 2 Diabetes Mellitus. Sci. Rep. 8, 16798. DOI: 10.1038/s41598-018-35009-y. Pretorius E, Bester J, Page MJ, Kell DB (2018): The potential of LPS-binding protein to reverse amyloid formation in plasma fibrin of individuals with Alzheimer-type dementia. Frontiers Aging Neurosci 10, 257. DOI: 10.3389/fnagi.2018.00257 Kell DB, Pretorius E (2018) To what extent are the terminal stages of sepsis, septic shock, SIRS, and multiple organ dysfunction syndrome actually driven by a toxic prion/amyloid form of fibrin? Semin Thromb Hemost 44, 224-238. PMID 28778104. DOI: 10.1055/s-0037-1604108. PRIZE for MOST VIEWED Open Access paper in the journal that year Kell DB, Pretorius E (2018) No effects without causes. The Iron Dysregulation and Dormant Microbes hypothesis for chronic, inflammatory diseases: evidence and consequences. Biol Rev 93, 1518-1557. PMID 29575574. doi: 10.1111/brv.12407 Pretorius E, Page MJ, Mbotwe S, Kell DB (2018) Lipopolysaccharide-binding protein (LBP) can reverse the amyloid state of fibrin seen or induced in Parkinson's disease. PlosOne 13, e0192121. DOI: 10.1371/journal.pone.0192121 Pretorius E, Page MJ, Hendricks L, Nkosi NB, Benson SR, Kell DB (2018) Both lipopolysaccharide and lipoteichoic acids potently induce anomalous fibrin amyloid formation: assessment with novel Amytracker™ stains. J R Soc Interface 20170941. Pubmed. DOI: 10.1098/rsif.2017.0941 Pretorius, E., Page, M.J., Engelbrecht, L., Ellis, G.C., and Kell, D.B. (2017). Substantial fibrin amyloidogenesis in type 2 diabetes assessed using amyloid-selective fluorescent stains. Cardiovasc Diabetol 16, 141. PMID 29096623. doi: https://doi.org/10.1186/s12933-017-0624-5. Pretorius E, Mbotwe S, Kell DB (2017) Lipopolysaccharide-binding protein (LBP) reverses the amyloid state of fibrin seen in plasma of type 2 diabetics with cardiovascular comorbidities. Sci Rep 7, 9680 doi:10.1038/s41598-017-09860-4 Pretorius E, Page MJ, Henricks L, Nkosi NB, Benson SR & Kell DB (2017) Both lipopolysaccharide and lipoteichoic acids potently induce anomalous fibrin amyloid formation: assessment with novel Amytracker™ stains. BioRxiv 143867. DOI: https://doi.org/10.1101/143867 Kell, D. B. & Pretorius, E. (2017). Proteins behaving badly. Substoichiometric molecular control and amplification of the initiation and nature of amyloid fibril formation: lessons from and for blood clotting. Progr Biophys Mol Biol 123, 16-41. PMID 27554450. DOI: 10.1016/j.pbiomolbio.2016.08.006. Pretorius, E., Akeredolu, O.-O., Soma, P. & Kell, D.B. (2017). Major involvement of bacterial components in rheumatoid arthritis and its accompanying oxidative stress, systemic inflammation and hypercoagulability. Exp Biol Med. 242, 355-373. PMID 27889698. DOI: 10.1177/1535370216681549 |
| Start Year | 2017 |
| Description | Channel 5 TV News Report |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Channel 5 investigative report "3/4 patients getting help for Long Covid didn't receive in-person appointment" that included an interview with Prof Douglas Kell regarding possible treatments. |
| Year(s) Of Engagement Activity | 2022 |
| URL | https://www.youtube.com/watch?v=O9XqLJgdksA |
| Description | Interview for International Journal (New Scientist) |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Contacted by New Scientist reporter to give interview relating to Microclots and Long COVID research. Continued reporting in this area is attracting international interest from researchers, funders and the press. Title of the article is "Chronic fatigue syndrome may be caused by mini-blood clots", published on 22 July 2022. Available from New Scientist via subscription only. |
| Year(s) Of Engagement Activity | 2022 |
| Description | Interview for International Journal (The Scientist) |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Title of the reported interview was "Trapped Inflammatory Molecules Contribute to Long COVID". Aim is to attract further interest and research funding. Lots of interest and funding applications in progress. |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://www.the-scientist.com/sponsored-article/trapped-inflammatory-molecules-contribute-to-long-co... |
| Description | Media report, national and international press (Mail Online and Bloomberg) |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Title of news report is "Covid survivors with symptoms weeks after infection have 'micro blood clots'". Picked up by the Daily Mail and Bloomberg following paper published in Cardiovascular Diabetology: "Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin" The research group is the first to have reported on finding micro clots in blood samples from individuals with long Covid using fluorescence microscopy and proteomics analysis. |
| Year(s) Of Engagement Activity | 2021 |
| URL | https://www.dailymail.co.uk/health/article-10057611/Covid-survivors-plagued-symptoms-weeks-beating-i... |
| Description | National news report |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | News report in The Times (subscription only) "Covid leaves wave of wearied souls in pandemic's wake" documenting latest Microclot and Long COVID research currently generating lots of interest from the media, patient groups and clinicians. |
| Year(s) Of Engagement Activity | 2022 |
| Description | Podcast |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | Podcast by and for Long Covid sufferers. Provided information on latest research. |
| Year(s) Of Engagement Activity | 2022 |
| URL | https://www.buzzsprout.com/1835170/10470844 |
| Description | Report in journal - Nature |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Article in Nature (subscription only), Vol 608, 25 August 2022 pages 662-664 - "The Mystery in Microclots". Publicising Microclot and Long COVID research. |
| Year(s) Of Engagement Activity | 2022 |
| Description | Review Article |
| Form Of Engagement Activity | A magazine, newsletter or online publication |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Article in Medical & Life Sciences Journal - "New research finds micro-clotting and inflammatory molecule abnormalities in long-COVID" - providing further information relating to this research. |
| Year(s) Of Engagement Activity | 2022 |
| URL | http://www.news-medical.net/news/20221018/New-research-finds-microclotting-and-inflammatory-molecule... |
| Description | YouTube Webinar |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Collaborative webinar via YouTube entitled "Covid Associated Coagulopathy - The Clot Thickens (or Not?)". |
| Year(s) Of Engagement Activity | 2022 |
| URL | https://www.youtube.com/watch?v=yyf7xunWydM |
| Description | YouTube broadcasts |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | A 3-part YouTube broadcast about Microclot and Long COVID research. Prompted lots of online engagement. Part 1 https://www.youtube.com/watch?v=2Q2tf9E3kzw - Microclots in Long COVID: The latest research Part 2 https://www.youtube.com/watch?v=nnUCNRpwhSI - How microclots fit into the Long COVID puzzle Part 3 https://www.youtube.com/watch?v=6q2WS4NuiBQ - Can nattokinase help break down microclots |
| Year(s) Of Engagement Activity | 2022 |
| URL | https://www.youtube.com/watch?v=2Q2tf9E3kzw |