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Publications (5 of 5) Show all publications
Becker, M., Conca, D. V., Dorma, N., Mistry, N., Hahlin, E., Frängsmyr, L., . . . Gerold, G. (2023). Efficient clathrin-mediated entry of enteric adenoviruses in human duodenal cells. Journal of Virology, 97(10)
Open this publication in new window or tab >>Efficient clathrin-mediated entry of enteric adenoviruses in human duodenal cells
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2023 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 97, no 10Article in journal (Refereed) Published
Abstract [en]

Enteric adenovirus types F40 and 41 (EAdVs) are a leading cause of diarrhea and diarrhea-associated death in young children and have recently been proposed to cause acute hepatitis in children. EAdVs have a unique capsid architecture and exhibit — unlike other human adenoviruses — a relatively strict tropism for gastrointestinal tissues with, to date, understudied infection mechanism and unknown target cells. In this study, we turn to potentially limiting host factors by comparing EAdV entry in cell lines with respiratory and intestinal origin by cellular perturbation, virus particle tracking, and transmission electron microscopy. Our analyses highlight kinetic advantages for EAdVs in duodenal HuTu80 cell infection and reveal a larger fraction of mobile particles, faster virus uptake, and infectious particle entry in intestinal cells. Moreover, EAdVs display a dependence on clathrin- and dynamin-dependent pathways in intestinal cells. Detailed knowledge of virus entry routes and host factor requirements is essential to understanding pathogenesis and developing new countermeasures. Hence, this study provides novel insights into the entry mechanisms of a medically important virus with emerging tropism in a cell line originating from a relevant tissue. IMPORTANCE Enteric adenoviruses have historically been difficult to grow in cell culture, which has resulted in lack of knowledge of host factors and pathways required for infection of these medically relevant viruses. Previous studies in non-intestinal cell lines showed slow infection kinetics and generated comparatively low virus yields compared to other adenovirus types. We suggest duodenum-derived HuTu80 cells as a superior cell line for studies to complement efforts using complex intestinal tissue models. We show that viral host cell factors required for virus entry differ between cell lines from distinct origins and demonstrate the importance of clathrin-mediated endocytosis.

Keywords
clathrin-mediated endocytosis, electron microscopy, enteric adenovirus, single particle tracking, virus entry
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-216662 (URN)10.1128/jvi.00770-23 (DOI)37823645 (PubMedID)2-s2.0-85175844402 (Scopus ID)
Funder
Swedish Research Council, 2020-06242Swedish Research Council, 2019-01472Knut and Alice Wallenberg FoundationKnut and Alice Wallenberg Foundation
Available from: 2023-11-27 Created: 2023-11-27 Last updated: 2024-07-02Bibliographically approved
Welén, K., Rosendal, E., Gisslén, M., Lenman, A., Freyhult, E., Fonseca Rodriguez, O., . . . Josefsson, A. (2022). A Phase 2 Trial of the Effect of Antiandrogen Therapy on COVID-19 Outcome: No Evidence of Benefit, Supported by Epidemiology and In Vitro Data. European Urology, 81(3), 285-293
Open this publication in new window or tab >>A Phase 2 Trial of the Effect of Antiandrogen Therapy on COVID-19 Outcome: No Evidence of Benefit, Supported by Epidemiology and In Vitro Data
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2022 (English)In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 81, no 3, p. 285-293Article in journal (Refereed) Published
Abstract [en]

Background: Men are more severely affected by COVID-19. Testosterone may influence SARS-CoV-2 infection and the immune response.

Objective: To clinically, epidemiologically, and experimentally evaluate the effect of antiandrogens on SARS-CoV-2 infection.

Designs, settings, and participants: A randomized phase 2 clinical trial (COVIDENZA) enrolled 42 hospitalized COVID-19 patients before safety evaluation. We also conducted a population-based retrospective study of 7894 SARS-CoV-2–positive prostate cancer patients and an experimental study using an air-liquid interface three-dimensional culture model of primary lung cells.

Intervention: In COVIDENZA, patients were randomized 2:1 to 5 d of enzalutamide or standard of care.

Outcome measurements: The primary outcomes in COVIDENZA were the time to mechanical ventilation or discharge from hospital. The population-based study investigated risk of hospitalization, intensive care, and death from COVID-19 after androgen inhibition.

Results and limitations: Enzalutamide-treated patients required longer hospitalization (hazard ratio [HR] for discharge from hospital 0.43, 95% confidence interval [CI] 0.20–0.93) and the trial was terminated early. In the epidemiological study, no preventive effects were observed. The frail population of patients treated with androgen deprivation therapy (ADT) in combination with abiraterone acetate or enzalutamide had a higher risk of dying from COVID-19 (HR 2.51, 95% CI 1.52–4.16). In vitro data showed no effect of enzalutamide on virus replication. The epidemiological study has limitations that include residual confounders.

Conclusions: The results do not support a therapeutic effect of enzalutamide or preventive effects of bicalutamide or ADT in COVID-19. Thus, these antiandrogens should not be used for hospitalized COVID-19 patients or as prevention for COVID-19. Further research on these therapeutics in this setting are not warranted.

Patient summary: We studied whether inhibition of testosterone could diminish COVID-19 symptoms. We found no evidence of an effect in a clinical study or in epidemiological or experimental investigations. We conclude that androgen inhibition should not be used for prevention or treatment of COVID-19.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
COVID-19, SARS-CoV-2, Antiandrogen, Randomized trial, Enzalutamide, Bicalutamide, Androgen deprivation therapy
National Category
Cancer and Oncology Public Health, Global Health, Social Medicine and Epidemiology Urology and Nephrology Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-190911 (URN)10.1016/j.eururo.2021.12.013 (DOI)000809752100020 ()2-s2.0-85122412349 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2020.0182ProstatacancerförbundetSwedish Cancer Society, 2017/478Swedish Cancer Society, 20 1055 PjFSwedish Heart Lung Foundation, 20200385Region Västerbotten, RV-836351Region Västerbotten, RV-939769
Available from: 2022-01-02 Created: 2022-01-02 Last updated: 2023-04-25Bibliographically approved
Rosendal, E., Mihai, I. S., Becker, M., Das, D., Frängsmyr, L., Persson, B. D., . . . Lenman, A. (2022). Serine protease inhibitors restrict host susceptibility to SARS-CoV-2 infections. mBio, 13(3), Article ID e00892-22.
Open this publication in new window or tab >>Serine protease inhibitors restrict host susceptibility to SARS-CoV-2 infections
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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
Keywords
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:nbn:se:umu:diva-203186 (URN)10.1128/mbio.00892-22 (DOI)000797888900001 ()35532162 (PubMedID)2-s2.0-85133144334 (Scopus ID)
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, 2016-06598
Available from: 2023-01-17 Created: 2023-01-17 Last updated: 2023-07-03Bibliographically approved
Zapatero-Belinchón, F. J., Moeller, R., Lasswitz, L., van Ham, M., Becker, M., Brogden, G., . . . Gerold, G. (2021). Fluvastatin mitigates SARS-CoV-2 infection in human lung cells. iScience, 24(12), Article ID 103469.
Open this publication in new window or tab >>Fluvastatin mitigates SARS-CoV-2 infection in human lung cells
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2021 (English)In: iScience, E-ISSN 2589-0042, Vol. 24, no 12, article id 103469Article in journal (Refereed) Published
Abstract [en]

Clinical data of patients suffering from COVID-19 indicates that statin therapy, used to treat hypercholesterolemia, is associated with a better disease outcome. Whether statins directly affect virus replication or influence the clinical outcome through modulation of immune responses is unknown. We therefore investigated the effect of statins on SARS-CoV-2 infection in human lung cells and found that only fluvastatin inhibited low and high pathogenic coronaviruses in vitro and ex vivo in a dose-dependent manner. Quantitative proteomics revealed that fluvastatin and other tested statins modulated the cholesterol synthesis pathway without altering innate antiviral immune responses in infected lung epithelial cells. However, fluvastatin treatment specifically downregulated proteins that modulate protein translation and viral replication. Collectively, these results support the notion that statin therapy poses no additional risk to individuals exposed to SARS-CoV-2 and that fluvastatin has a moderate beneficial effect on SARS-CoV-2 infection of human lung cells.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Drugs, Virology
National Category
Infectious Medicine Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-190104 (URN)10.1016/j.isci.2021.103469 (DOI)000740245300008 ()2-s2.0-85120182160 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationEU, Horizon 2020, 871029
Available from: 2021-12-10 Created: 2021-12-10 Last updated: 2024-07-02Bibliographically approved
Rajan, A., Palm, E., Trulsson, F., Mundigl, S., Becker, M., Persson, D., . . . Lenman, A. (2021). Heparan Sulfate Is a Cellular Receptor for Enteric Human Adenoviruses. Viruses, 13(2), Article ID 298.
Open this publication in new window or tab >>Heparan Sulfate Is a Cellular Receptor for Enteric Human Adenoviruses
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2021 (English)In: Viruses, E-ISSN 1999-4915, Vol. 13, no 2, article id 298Article in journal (Refereed) Published
Abstract [en]

Human adenovirus (HAdV)-F40 and -F41 are leading causes of diarrhea and diarrhea-associated mortality in children under the age of five, but the mechanisms by which they infect host cells are poorly understood. HAdVs initiate infection through interactions between the knob domain of the fiber capsid protein and host cell receptors. Unlike most other HAdVs, HAdV-F40 and -F41 possess two different fiber proteins-a long fiber and a short fiber. Whereas the long fiber binds to the Coxsackievirus and adenovirus receptor (CAR), no binding partners have been identified for the short fiber. In this study, we identified heparan sulfate (HS) as an interaction partner for the short fiber of enteric HAdVs. We demonstrate that exposure to acidic pH, which mimics the environment of the stomach, inactivates the interaction of enteric adenovirus with CAR. However, the short fiber:HS interaction is resistant to and even enhanced by acidic pH, which allows attachment to host cells. Our results suggest a switch in receptor usage of enteric HAdVs after exposure to acidic pH and add to the understanding of the function of the short fibers. These results may also be useful for antiviral drug development and the utilization of enteric HAdVs for clinical applications such as vaccine development.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
capsid proteins, enteric adenovirus, fiber knobs, heparan sulfate, short fibers
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-181795 (URN)10.3390/v13020298 (DOI)000623302300001 ()2-s2.0-85102606288 (Scopus ID)
Available from: 2021-04-01 Created: 2021-04-01 Last updated: 2024-01-17Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3634-066x

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