Common Genetic Variation in Humans Impacts In Vitro Susceptibility to SARS-CoV-2 Infection

Overview

Journal Stem Cell Reports

Publisher Cell Press

Specialty Cell Biology

Date 2021 Feb 26

PMID 33636110

Citations 35

Authors

Kristina Dobrindt

Daisy A Hoagland

Carina Seah

Bibi Kassim

Callan P OShea

Aleta Murphy

Marina Iskhakova

Michael B Fernando

Samuel K Powell

P J Michael Deans

Ben Javidfar

Cyril Peter

Rasmus Moller

Skyler A Uhl

Meilin Fernandez Garcia

Masaki Kimura

Kentaro Iwasawa

John F Crary

Darrell N Kotton

Takanori Takebe

Laura M Huckins

Benjamin R tenOever

Schahram Akbarian

Kristen J Brennand

Affiliations

Soon will be listed here.

Abstract

The host response to SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, demonstrates significant interindividual variability. In addition to showing more disease in males, the elderly, and individuals with underlying comorbidities, SARS-CoV-2 can seemingly afflict healthy individuals with profound clinical complications. We hypothesize that, in addition to viral load and host antibody repertoire, host genetic variants influence vulnerability to infection. Here we apply human induced pluripotent stem cell (hiPSC)-based models and CRISPR engineering to explore the host genetics of SARS-CoV-2. We demonstrate that a single-nucleotide polymorphism (rs4702), common in the population and located in the 3' UTR of the protease FURIN, influences alveolar and neuron infection by SARS-CoV-2 in vitro. Thus, we provide a proof-of-principle finding that common genetic variation can have an impact on viral infection and thus contribute to clinical heterogeneity in COVID-19. Ongoing genetic studies will help to identify high-risk individuals, predict clinical complications, and facilitate the discovery of drugs.

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References

Koike H, Iwasawa K, Ouchi R, Maezawa M, Giesbrecht K, Saiki N . Modelling human hepato-biliary-pancreatic organogenesis from the foregut-midgut boundary. Nature. 2019; 574(7776):112-116. PMC: 7643931. DOI: 10.1038/s41586-019-1598-0. View

Yuan M, Wu N, Zhu X, Lee C, So R, Lv H . A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV. Science. 2020; 368(6491):630-633. PMC: 7164391. DOI: 10.1126/science.abb7269. View

Pavlovic B, Blake L, Roux J, Chavarria C, Gilad Y . A Comparative Assessment of Human and Chimpanzee iPSC-derived Cardiomyocytes with Primary Heart Tissues. Sci Rep. 2018; 8(1):15312. PMC: 6193013. DOI: 10.1038/s41598-018-33478-9. View

Shelton J, Shastri A, Ye C, Weldon C, Filshtein-Sonmez T, Coker D . Trans-ancestry analysis reveals genetic and nongenetic associations with COVID-19 susceptibility and severity. Nat Genet. 2021; 53(6):801-808. DOI: 10.1038/s41588-021-00854-7. View

Kenney A, Dowdle J, Bozzacco L, McMichael T, St Gelais C, Panfil A . Human Genetic Determinants of Viral Diseases. Annu Rev Genet. 2017; 51:241-263. PMC: 6038703. DOI: 10.1146/annurev-genet-120116-023425. View

Wruck W, Adjaye J . SARS-CoV-2 receptor ACE2 is co-expressed with genes related to transmembrane serine proteases, viral entry, immunity and cellular stress. Sci Rep. 2020; 10(1):21415. PMC: 7723043. DOI: 10.1038/s41598-020-78402-2. View

Wrapp D, Wang N, Corbett K, Goldsmith J, Hsieh C, Abiona O . Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020; 367(6483):1260-1263. PMC: 7164637. DOI: 10.1126/science.abb2507. View

Ramani A, Muller L, Ostermann P, Gabriel E, Abida-Islam P, Muller-Schiffmann A . SARS-CoV-2 targets neurons of 3D human brain organoids. EMBO J. 2020; 39(20):e106230. PMC: 7560208. DOI: 10.15252/embj.2020106230. View

Li Y, Bai W, Hashikawa T . The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020; 92(6):552-555. PMC: 7228394. DOI: 10.1002/jmv.25728. View

10.

Ellinghaus D, Degenhardt F, Bujanda L, Buti M, Albillos A, Invernizzi P . Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N Engl J Med. 2020; 383(16):1522-1534. PMC: 7315890. DOI: 10.1056/NEJMoa2020283. View

11.

Shilts J, Crozier T, Greenwood E, Lehner P, Wright G . No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor. Sci Rep. 2021; 11(1):413. PMC: 7801465. DOI: 10.1038/s41598-020-80464-1. View

12.

Ramlall V, Thangaraj P, Meydan C, Foox J, Butler D, Kim J . Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection. Nat Med. 2020; 26(10):1609-1615. PMC: 7809634. DOI: 10.1038/s41591-020-1021-2. View

13.

Pilotto A, Odolini S, Masciocchi S, Comelli A, Volonghi I, Gazzina S . Steroid-Responsive Encephalitis in Coronavirus Disease 2019. Ann Neurol. 2020; 88(2):423-427. PMC: 7276848. DOI: 10.1002/ana.25783. View

14.

Ludvigsson J . Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr. 2020; 109(6):1088-1095. PMC: 7228328. DOI: 10.1111/apa.15270. View

15.

Guan W, Ni Z, Hu Y, Liang W, Ou C, He J . Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020; 382(18):1708-1720. PMC: 7092819. DOI: 10.1056/NEJMoa2002032. View

16.

Russo R, Andolfo I, Lasorsa V, Iolascon A, Capasso M . Genetic Analysis of the Coronavirus SARS-CoV-2 Host Protease in Different Populations. Front Genet. 2020; 11:872. PMC: 7417663. DOI: 10.3389/fgene.2020.00872. View

17.

Dobrindt K, Zhang H, Das D, Abdollahi S, Prorok T, Ghosh S . Publicly Available hiPSC Lines with Extreme Polygenic Risk Scores for Modeling Schizophrenia. Complex Psychiatry. 2021; 6(3-4):68-82. PMC: 7923934. DOI: 10.1159/000512716. View

18.

Lindesmith L, Moe C, Marionneau S, Ruvoen N, Jiang X, Lindblad L . Human susceptibility and resistance to Norwalk virus infection. Nat Med. 2003; 9(5):548-53. DOI: 10.1038/nm860. View

19.

Dixit A, Parnas O, Li B, Chen J, Fulco C, Jerby-Arnon L . Perturb-Seq: Dissecting Molecular Circuits with Scalable Single-Cell RNA Profiling of Pooled Genetic Screens. Cell. 2016; 167(7):1853-1866.e17. PMC: 5181115. DOI: 10.1016/j.cell.2016.11.038. View

20.

Schrode N, Ho S, Yamamuro K, Dobbyn A, Huckins L, Matos M . Synergistic effects of common schizophrenia risk variants. Nat Genet. 2019; 51(10):1475-1485. PMC: 6778520. DOI: 10.1038/s41588-019-0497-5. View