scholarly journals A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Mohd Anisul ◽  
Jarrod Shilts ◽  
Jeremy Schwartzentruber ◽  
James Hayhurst ◽  
Annalisa Buniello ◽  
...  
Keyword(s):  
Open Access ◽  
Clinical Relevance ◽  
Research Council ◽  
Medical Research Council ◽  
Spike Protein ◽  
Mendelian Randomisation ◽  
Host Proteins ◽  
Genetic Investigation ◽  
Soluble Fas ◽  
The Uk

Background: The virus SARS-CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19.Methods: To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome-wide genetic colocalisation tests, and polygenic (pan) and cis-Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets.Results: Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble Fas (colocalisation probability > 0.9, p = 1 x 10-4), implicating Fas-mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis-Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic and a look-up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19.Conclusions: Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19.Funding: MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

scholarly journals A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance

2021 ◽  
Author(s):  
Mohd A Karim ◽  
Jarrod Shilts ◽  
Jeremy Schwartzentruber ◽  
James Hayhurst ◽  
Annalisa Buniello ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Clinical Relevance ◽  
Plasma Concentrations ◽  
Spike Protein ◽  
Coagulation Cascade ◽  
Interferon Response ◽  
Mendelian Randomisation ◽  
Host Proteins ◽  
Genetic Investigation ◽  
Soluble Fas

AbstractThe virus SARS-CoV-2 can exploit biological vulnerabilities in susceptible hosts that predispose to development of severe COVID-19. Previous reports have identified several host proteins related to the interferon response (e.g. OAS1), interleukin-6 signalling (IL-6R), and the coagulation cascade (linked via ABO) that were associated with risk of COVID-19. In the present study, we performed proteome-wide genetic colocalisation tests leveraging publicly available protein and COVID-19 datasets, to identify additional proteins that may contribute to COVID-19 risk. Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble FAS (colocalisation probability > 0.9, p = 1 × 10−4), implicating FAS-mediated apoptosis as a potential target for COVID-19 risk. We also undertook polygenic (pan) and cis-Mendelian randomisation analyses that showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal was associated with plasma concentrations of several proteins, with the strongest association observed with CD209 in several proteomic datasets. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19. Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19.

scholarly journals Isabella Helen Mary Muir CBE. 20 August 1920—28 November 2005

2018 ◽  
Vol 65 ◽  
pp. 283-298
Author(s):  
Tim Hardingham
Keyword(s):  
Biomedical Research ◽  
Molecular Basis ◽  
Research Council ◽  
Medical Research Council ◽  
Joint Diseases ◽  
Wear And Tear ◽  
Active Processes ◽  
Kennedy Institute ◽  
The Uk ◽  
Research Analysis

Helen Muir was a leader in British biomedical research over many years. She trained as a chemist at Oxford and, having started her research on the structure of penicillin, she moved progressively into biomedical research. Helen's major achievements were in research on joint diseases, particularly osteoarthritis, which affects 8 million sufferers in the UK. She identified the molecular basis of the key load-bearing properties of cartilage in our joints and helped to establish that osteoarthritis was driven by active processes and not just wear and tear. This revolutionized research approaches at the time and the consequences are important to this day. Her careful research analysis laid the foundation for molecular cellular research approaches to degenerative joint diseases. She was Division Head and then Director at the Kennedy Institute for Rheumatology in Hammersmith, London. Helen was highly regarded and was appointed the first woman member of the Medical Research Council and later a Trustee of the Wellcome Trust. She was respected for her opinions, which she expressed in a forthright manner. She was very much without prejudice and judged people on their merits. She could not stand pomposity and, although she became a grand lady, she always had a wry sense of humour and liked a good laugh.

Sign in / Sign up

Export Citation Format

Share Document