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Publications (10 of 17) Show all publications
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
Persson, B. D., Nord, S., Lindquist, R., Danskog, K., Överby, A. K., Kohl, A., . . . Arnberg, N. (2021). BAF45b is required for efficient zika virus infection of HAP1 cells. Viruses, 13(10), Article ID 2007.
Open this publication in new window or tab >>BAF45b is required for efficient zika virus infection of HAP1 cells
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2021 (English)In: Viruses, E-ISSN 1999-4915, Vol. 13, no 10, article id 2007Article in journal (Refereed) Published
Abstract [en]

The 2016 Zika virus (ZIKV) epidemic illustrates the impact of flaviviruses as emerging human pathogens. For unknown reasons, ZIKV replicates more efficiently in neural progenitor cells (NPCs) than in postmitotic neurons. Here, we identified host factors used by ZIKV using the NCI-60 library of cell lines and COMPARE analysis, and cross-analyzed this library with two other libraries of host factors with importance for ZIKV infection. We identified BAF45b, a subunit of the BAF (Brg1/Brm-associated factors) protein complexes that regulate differentiation of NPCs to post-mitotic neurons. ZIKV (and other flaviviruses) infected HAP1 cells deficient in expression of BAF45b and other BAF subunits less efficiently than wildtype (WT) HAP1 cells. We concluded that subunits of the BAF complex are important for infection of ZIKV and other flavivirus. Given their function in cell and tissue differentiation, such regulators may be important determinants of tropism and pathogenesis of arthropod-borne flaviviruses.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
BAF45b, DPF1, Flavivirus, Zika virus
National Category
Microbiology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-188850 (URN)10.3390/v13102007 (DOI)000792951900009 ()2-s2.0-85117010328 (Scopus ID)
Funder
EU, Horizon 2020, 734584Swedish Research Council, 2017-02438Swedish Research Council, 2016-00968
Available from: 2021-10-25 Created: 2021-10-25 Last updated: 2024-01-17Bibliographically 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: 2023-11-28Bibliographically 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
Arnberg, N. & Lenman, A. (2021). Special issue "adenovirus pathogenesis". Viruses, 13(6), Article ID 1112.
Open this publication in new window or tab >>Special issue "adenovirus pathogenesis"
2021 (English)In: Viruses, E-ISSN 1999-4915, Vol. 13, no 6, article id 1112Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
MDPI, 2021
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-185675 (URN)10.3390/v13061112 (DOI)2-s2.0-85108591525 (Scopus ID)
Available from: 2021-07-02 Created: 2021-07-02 Last updated: 2024-01-17Bibliographically approved
Kirui, J., Abidine, Y., Lenman, A., Islam, M. K. K., Yong-Dae, G., Lasswitz, L., . . . Gerold, G. (2021). The Phosphatidylserine Receptor TIM-1 Enhances Authentic Chikungunya Virus Cell Entry. Cells, 10(7), Article ID 1828.
Open this publication in new window or tab >>The Phosphatidylserine Receptor TIM-1 Enhances Authentic Chikungunya Virus Cell Entry
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2021 (English)In: Cells, E-ISSN 2073-4409, Vol. 10, no 7, article id 1828Article in journal (Refereed) Published
Abstract [en]

Chikungunya virus (CHIKV) is a re-emerging, mosquito-transmitted, enveloped positive stranded RNA virus. Chikungunya fever is characterized by acute and chronic debilitating arthritis. Although multiple host factors have been shown to enhance CHIKV infection, the molecular mechanisms of cell entry and entry factors remain poorly understood. The phosphatidylserine-dependent receptors, T-cell immunoglobulin and mucin domain 1 (TIM-1) and Axl receptor tyrosine kinase (Axl), are transmembrane proteins that can serve as entry factors for enveloped viruses. Previous studies used pseudoviruses to delineate the role of TIM-1 and Axl in CHIKV entry. Conversely, here, we use the authentic CHIKV and cells ectopically expressing TIM-1 or Axl and demonstrate a role for TIM-1 in CHIKV infection. To further characterize TIM-1-dependent CHIKV infection, we generated cells expressing domain mutants of TIM-1. We show that point mutations in the phosphatidylserine binding site of TIM-1 lead to reduced cell binding, entry, and infection of CHIKV. Ectopic expression of TIM-1 renders immortalized keratinocytes permissive to CHIKV, whereas silencing of endogenously expressed TIM-1 in human hepatoma cells reduces CHIKV infection. Altogether, our findings indicate that, unlike Axl, TIM-1 readily promotes the productive entry of authentic CHIKV into target cells.

Place, publisher, year, edition, pages
MDPI, 2021
Keywords
Chikungunya virus, CHIKV, alphavirus, enveloped virus, phosphatidylserine, T-cell immunoglobulin and mucin domain 1, TIM-1, Axl receptor tyrosine kinase, Axl, entry
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-187299 (URN)10.3390/cells10071828 (DOI)000676394100001 ()34359995 (PubMedID)2-s2.0-85114081934 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research Council, 2017-05607
Available from: 2021-09-09 Created: 2021-09-09 Last updated: 2021-09-09Bibliographically approved
Rafie, K., Lenman, A., Fuchs, J., Rajan, A., Arnberg, N. & Carlson, L.-A. (2021). The structure of enteric human adenovirus 41: A leading cause of diarrhea in children. Science Advances, 7(2), Article ID eabe0974.
Open this publication in new window or tab >>The structure of enteric human adenovirus 41: A leading cause of diarrhea in children
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2021 (English)In: Science Advances, E-ISSN 2375-2548, Vol. 7, no 2, article id eabe0974Article in journal (Refereed) Published
Abstract [en]

Human adenovirus (HAdV) types F40 and F41 are a prominent cause of diarrhea and diarrhea-associated mortality in young children worldwide. These enteric HAdVs differ notably in tissue tropism and pathogenicity from respiratory and ocular adenoviruses, but the structural basis for this divergence has been unknown. Here, we present the first structure of an enteric HAdV-HAdV-F41-determined by cryo-electron microscopy to a resolution of 3.8 angstrom. The structure reveals extensive alterations to the virion exterior as compared to nonenteric HAdVs, including a unique arrangement of capsid protein IX. The structure also provides new insights into conserved aspects of HAdV architecture such as a proposed location of core protein V, which links the viral DNA to the capsid, and assembly-induced conformational changes in the penton base protein. Our findings provide the structural basis for adaptation of enteric HAdVs to a fundamentally different tissue tropism.

Place, publisher, year, edition, pages
American Association for the Advancement of Science, 2021
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-180151 (URN)10.1126/sciadv.abe0974 (DOI)000606331400035 ()33523995 (PubMedID)2-s2.0-85099241558 (Scopus ID)
Available from: 2021-03-01 Created: 2021-03-01 Last updated: 2023-03-24Bibliographically approved
Palor, M., Stejskal, L., Mandal, P., Lenman, A., Alberione, M. P., Kirui, J., . . . Grove, J. (2020). Cholesterol sensing by CD81 is important for hepatitis C virus entry. Journal of Biological Chemistry, 295(50), 16931-16948
Open this publication in new window or tab >>Cholesterol sensing by CD81 is important for hepatitis C virus entry
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2020 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 295, no 50, p. 16931-16948Article in journal (Refereed) Published
Abstract [en]

CD81 plays a role in a variety of physiological and pathological processes. Recent structural analysis of CD81 indicates that it contains an intramembrane cholesterol-binding pocket and that interaction with cholesterol may regulate a conformational switch in the extracellular domain of CD81. Therefore, CD81 possesses a potential cholesterol sensing mechanism; however, its relevance for protein function is thus far unknown. In this study we investigate CD81 cholesterol sensing in the context of its activity as a receptor for hepatitis C virus. Structure-led mutagenesis of the cholesterol-binding pocket reduced CD81-cholesterol association, but had disparate effects on HCV, both reducing and enhancing CD81 receptor activity. We reasoned that this could be explained by alterations in the consequences of cholesterol binding. To investigate this further we performed molecular dynamic simulations of CD81 with and without cholesterol; this identified an allosteric mechanism by which cholesterol binding regulates the conformation of CD81. To test this, we designed further mutations to force CD81 into either the open (cholesterol unbound) or closed (cholesterol bound) conformation. The open mutant of CD81 exhibited reduced receptor activity whereas the closed mutant was enhanced. These data are consistent with cholesterol switching CD81 between a receptor active and inactive state. CD81 interactome analysis also suggests that conformational switching may modulate the assembly of CD81-partner networks. This work furthers our understanding of the molecular mechanism of CD81 cholesterol sensing, how this relates to HCV entry and CD81's function as a molecular scaffold; these insights are relevant to CD81's varied roles in health and disease.

Place, publisher, year, edition, pages
Elsevier, 2020
Keywords
Hepatitis C virus (HCV), cholesterol-binding protein, molecular dynamics, tetraspanin, virus entry
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-176974 (URN)10.1074/jbc.RA120.014761 (DOI)000599868700004 ()32900848 (PubMedID)2-s2.0-85097582734 (Scopus ID)
Funder
Wellcome trustKnut and Alice Wallenberg Foundation
Available from: 2020-11-23 Created: 2020-11-23 Last updated: 2023-11-28Bibliographically approved
Persson, D., Lenman, A., Frängsmyr, L., Schmid, M., Ahlm, C., Plückthun, A., . . . Arnberg, N. (2020). Lactoferrin-Hexon Interactions Mediate CAR-Independent Adenovirus Infection of Human Respiratory Cells. Journal of Virology, 94(14), Article ID e00542-20.
Open this publication in new window or tab >>Lactoferrin-Hexon Interactions Mediate CAR-Independent Adenovirus Infection of Human Respiratory Cells
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2020 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 94, no 14, article id e00542-20Article in journal (Refereed) Published
Abstract [en]

Virus entry into host cells is a complex process that is largely regulated by access to specific cellular receptors. Human adenoviruses (HAdVs) and many other viruses use cell adhesion molecules such as the coxsackievirus and adenovirus receptor (CAR) for attachment to and entry into target cells. These molecules are rarely expressed on the apical side of polarized epithelial cells, which raises the question of how adenoviruses—and other viruses that engage cell adhesion molecules—enter polarized cells from the apical side to initiate infection. We have previously shown that species C HAdVs utilize lactoferrin—a common innate immune component secreted to respiratory mucosa—for infection via unknown mechanisms. Using a series of biochemical, cellular, and molecular biology approaches, we mapped this effect to the proteolytically cleavable, positively charged, N-terminal 49 residues of human lactoferrin (hLF) known as human lactoferricin (hLfcin). Lactoferricin (Lfcin) binds to the hexon protein on the viral capsid and anchors the virus to an unknown receptor structure of target cells, resulting in infection. These findings suggest that HAdVs use distinct cell entry mechanisms at different stages of infection. To initiate infection, entry is likely to occur at the apical side of polarized epithelial cells, largely by means of hLF and hLfcin bridging HAdV capsids via hexons to as-yet-unknown receptors; when infection is established, progeny virions released from the basolateral side enter neighboring cells by means of hLF/hLfcin and CAR in parallel.

IMPORTANCE: Many viruses enter target cells using cell adhesion molecules as receptors. Paradoxically, these molecules are abundant on the lateral and basolateral side of intact, polarized, epithelial target cells, but absent on the apical side that must be penetrated by incoming viruses to initiate infection. Our study provides a model whereby viruses use different mechanisms to infect polarized epithelial cells depending on which side of the cell—apical or lateral/basolateral—is attacked. This study may also be useful to understand the biology of other viruses that use cell adhesion molecules as receptors.

Place, publisher, year, edition, pages
American Society for Microbiology, 2020
Keywords
adenovirus, CAR, cellular receptor, lactoferrin, tropism
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-173890 (URN)10.1128/JVI.00542-20 (DOI)000550190300011 ()32376620 (PubMedID)2-s2.0-85087533884 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2013.0019
Available from: 2020-08-06 Created: 2020-08-06 Last updated: 2023-03-24Bibliographically approved
Organisations
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ORCID iD: ORCID iD iconorcid.org/0000-0001-5109-9408

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