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Serine protease inhibitors restrict host susceptibility to SARS-CoV-2 infections
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).ORCID iD: 0000-0001-8512-0535
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). National Clinical Research School in Chronic Inflammatory Diseases (NCRSCID), Karolinska Institutet, Solna, Sweden.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between The Medical School Hannover, The Helmholtz Centre for Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.ORCID iD: 0000-0002-3634-066x
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
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2022 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 13, no 3, article id e00892-22Article in journal (Refereed) Published
Abstract [en]

The coronavirus disease 2019, COVID-19, is a complex disease with a wide range of symptoms from asymptomatic infections to severe acute respiratory syndrome with lethal outcome. Individual factors such as age, sex, and comorbidities increase the risk for severe infections, but other aspects, such as genetic variations, are also likely to affect the susceptibility to SARS-CoV-2 infection and disease severity. Here, we used a human 3D lung cell model based on primary cells derived from multiple donors to identity host factors that regulate SARS-CoV-2 infection. With a transcriptomics-based approach, we found that less susceptible donors show a higher expression level of serine protease inhibitors SERPINA1, SERPINE1, and SERPINE2, identifying variation in cellular serpin levels as restricting host factors for SARS-CoV-2 infection. We pinpoint their antiviral mechanism of action to inhibition of the cellular serine protease, TMPRSS2, thereby preventing cleavage of the viral spike protein and TMPRSS2-mediated entry into the target cells. By means of single-cell RNA sequencing, we further locate the expression of the individual serpins to basal, ciliated, club, and goblet cells. Our results add to the importance of genetic variations as determinants for SARS-CoV-2 susceptibility and suggest that genetic deficiencies of cellular serpins might represent risk factors for severe COVID-19. Our study further highlights TMPRSS2 as a promising target for antiviral intervention and opens the door for the usage of locally administered serpins as a treatment against COVID-19.

Place, publisher, year, edition, pages
American Society for Microbiology, 2022. Vol. 13, no 3, article id e00892-22
Keywords [en]
A1AT, alpha-1-antitrypsin, antithrombin III, ATIII, COVID-19, PAI1, plasminogen activator inhibitor 1, SARS-CoV-2, serpin, TMPRSS2
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:umu:diva-203186DOI: 10.1128/mbio.00892-22ISI: 000797888900001PubMedID: 35532162Scopus ID: 2-s2.0-85133144334OAI: oai:DiVA.org:umu-203186DiVA, id: diva2:1727739
Funder
Science for Life Laboratory, SciLifeLabSwedish National Infrastructure for Computing (SNIC), SNIC 2020/6-251Swedish Heart Lung Foundation, 2020038Knut and Alice Wallenberg Foundation, 2020.0182Knut and Alice Wallenberg Foundation, C19R:028Swedish Society for Medical Research (SSMF)The Kempe Foundations, JCK-1827Swedish Research Council, 2016-06598Available from: 2023-01-17 Created: 2023-01-17 Last updated: 2023-07-03Bibliographically approved

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Rosendal, EbbaMihai, Ionut SebastianBecker, MiriamDas, DebojyotiFrängsmyr, LarsPersson, B. DavidRankin, GregoryGröning, RemigiusTrygg, JohanForsell, MattiasBlomberg, AndersHenriksson, JohanÖverby, Anna K.Lenman, Annasara

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Rosendal, EbbaMihai, Ionut SebastianBecker, MiriamDas, DebojyotiFrängsmyr, LarsPersson, B. DavidRankin, GregoryGröning, RemigiusTrygg, JohanForsell, MattiasBlomberg, AndersHenriksson, JohanÖverby, Anna K.Lenman, Annasara
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Department of Clinical MicrobiologyMolecular Infection Medicine Sweden (MIMS)Department of Molecular Biology (Faculty of Medicine)Wallenberg Centre for Molecular Medicine at Umeå University (WCMM)Section of MedicineDepartment of Chemistry
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