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

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 pro...

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Published in:	Stem cell reports Vol. 16; no. 3; pp. 505 - 518
Main Authors:	Dobrindt, Kristina, Hoagland, Daisy A., Seah, Carina, Kassim, Bibi, O'Shea, Callan P., Murphy, Aleta, Iskhakova, Marina, Fernando, Michael B., Powell, Samuel K., Deans, P.J. Michael, Javidfar, Ben, Peter, Cyril, Møller, Rasmus, Uhl, Skyler A., Garcia, Meilin Fernandez, Kimura, Masaki, Iwasawa, Kentaro, Crary, John F., Kotton, Darrell N., Takebe, Takanori, Huckins, Laura M., tenOever, Benjamin R., Akbarian, Schahram, Brennand, Kristen J.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 09-03-2021 Elsevier
Subjects:	3' Untranslated Regions - genetics Adolescent Adult Animals brain Cell Line Chlorocebus aethiops Clustered Regularly Interspaced Short Palindromic Repeats - genetics COVID-19 - genetics COVID-19 - virology Female Furin - genetics FURIN rs4702 Genetic Predisposition to Disease - genetics host genetics Host-Pathogen Interactions - genetics human induced pluripotent stem cell Humans Induced Pluripotent Stem Cells - virology Male neurons Neurons - virology Peptide Hydrolases - genetics Polymorphism, Single Nucleotide - genetics SARS-CoV-2 SARS-CoV-2 - pathogenicity Vero Cells human induced pluripotent stem cell host genetics SARS-CoV-2 FURIN rs4702 brain neurons
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Summary:	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. [Display omitted] •hiPSC-derived model of SARS-CoV-2 infection in human neurons, lung, and intestinal cells•Infection of post-mitotic human neurons by SARS-CoV-2•Effect of host gene expression (ACE2, FURIN, BSG, and TMPRSS2) on SARS-CoV-2 infection•Impact of host genotype with common SNP rs4702 on SARS-CoV-2 infection Brennand, Akbarian, and colleagues combine human induced pluripotent stem cell-based models and CRISPR engineering to explore the host genetics of SARS-CoV-2 in alveolar cells, intestinal cells, and neurons. A SNP(rs4702) located in the 3′ UTR of the protease FURIN influences alveolar and neuron infection by SARS-CoV-2 in vitro.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Department of Psychiatry, Yale University, New Haven, CT 06511, USA These authors contributed equally
ISSN:	2213-6711 2213-6711
DOI:	10.1016/j.stemcr.2021.02.010