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Marc J. Eleveld
Section Paediatric Infectious Diseases, Laboratory of Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands

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Journal article
Published: 11 February 2021 in Viruses
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a new human pathogen in late 2019 and it has infected over 100 million people in less than a year. There is a clear need for effective antiviral drugs to complement current preventive measures, including vaccines. In this study, we demonstrate that berberine and obatoclax, two broad-spectrum antiviral compounds, are effective against multiple isolates of SARS-CoV-2. Berberine, a plant-derived alkaloid, inhibited SARS-CoV-2 at low micromolar concentrations and obatoclax, which was originally developed as an anti-apoptotic protein antagonist, was effective at sub-micromolar concentrations. Time-of-addition studies indicated that berberine acts on the late stage of the viral life cycle. In agreement, berberine mildly affected viral RNA synthesis, but it strongly reduced infectious viral titers, leading to an increase in the particle-to-pfu ratio. In contrast, obatoclax acted at the early stage of the infection, which is in line with its activity to neutralize the acidic environment in endosomes. We assessed infection of primary human nasal epithelial cells that were cultured on an air-liquid interface and found that SARS-CoV-2 infection induced and repressed expression of specific sets of cytokines and chemokines. Moreover, both obatoclax and berberine inhibited SARS-CoV-2 replication in these primary target cells. We propose berberine and obatoclax as potential antiviral drugs against SARS-CoV-2 that could be considered for further efficacy testing.

ACS Style

Finny Varghese; Esther van Woudenbergh; Gijs Overheul; Marc Eleveld; Lisa Kurver; Niels van Heerbeek; Arjan van Laarhoven; Pascal Miesen; Gerco Den Hartog; Marien de Jonge; Ronald van Rij. Berberine and Obatoclax Inhibit SARS-Cov-2 Replication in Primary Human Nasal Epithelial Cells In Vitro. Viruses 2021, 13, 282 .

AMA Style

Finny Varghese, Esther van Woudenbergh, Gijs Overheul, Marc Eleveld, Lisa Kurver, Niels van Heerbeek, Arjan van Laarhoven, Pascal Miesen, Gerco Den Hartog, Marien de Jonge, Ronald van Rij. Berberine and Obatoclax Inhibit SARS-Cov-2 Replication in Primary Human Nasal Epithelial Cells In Vitro. Viruses. 2021; 13 (2):282.

Chicago/Turabian Style

Finny Varghese; Esther van Woudenbergh; Gijs Overheul; Marc Eleveld; Lisa Kurver; Niels van Heerbeek; Arjan van Laarhoven; Pascal Miesen; Gerco Den Hartog; Marien de Jonge; Ronald van Rij. 2021. "Berberine and Obatoclax Inhibit SARS-Cov-2 Replication in Primary Human Nasal Epithelial Cells In Vitro." Viruses 13, no. 2: 282.

Preprint content
Published: 24 December 2020
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a new human pathogen in late 2019 and has infected an estimated 10% of the global population in less than a year. There is a clear need for effective antiviral drugs to complement current preventive measures including vaccines. In this study, we demonstrate that berberine and obatoclax, two broad-spectrum antiviral compounds, are effective against multiple isolates of SARS-CoV-2. Berberine, a plant-derived alkaloid, inhibited SARS-CoV-2 at low micromolar concentrations and obatoclax, originally developed as an anti-apoptotic protein antagonist, was effective at sub-micromolar concentrations. Time-of-addition studies indicated that berberine acts on the late stage of the viral life cycle. In agreement, berberine mildly affected viral RNA synthesis, but strongly reduced infectious viral titers, leading to an increase in the particle-to-pfu ratio. In contrast, obatoclax acted at the early stage of the infection, in line with its activity to neutralize the acidic environment in endosomes. We assessed infection of primary human nasal epithelial cells cultured on an air-liquid interface and found that SARS-CoV-2 infection induced and repressed expression of a specific set of cytokines and chemokines. Moreover, both obatoclax and berberine inhibited SARS-CoV-2 replication in these primary target cells. We propose berberine and obatoclax as potential antiviral drugs against SARS-CoV-2 that could be considered for further efficacy testing.

ACS Style

Finny S. Varghese; Esther van Woudenbergh; Gijs J. Overheul; Marc J. Eleveld; Lisa Kurver; Niels van Heerbeek; Arjan van Laarhoven; Pascal Miesen; Gerco Den Hartog; Marien I. de Jonge; Ronald P. van Rij. Berberine and obatoclax inhibit SARS-CoV-2 replication in primary human nasal epithelial cells in vitro. 2020, 1 .

AMA Style

Finny S. Varghese, Esther van Woudenbergh, Gijs J. Overheul, Marc J. Eleveld, Lisa Kurver, Niels van Heerbeek, Arjan van Laarhoven, Pascal Miesen, Gerco Den Hartog, Marien I. de Jonge, Ronald P. van Rij. Berberine and obatoclax inhibit SARS-CoV-2 replication in primary human nasal epithelial cells in vitro. . 2020; ():1.

Chicago/Turabian Style

Finny S. Varghese; Esther van Woudenbergh; Gijs J. Overheul; Marc J. Eleveld; Lisa Kurver; Niels van Heerbeek; Arjan van Laarhoven; Pascal Miesen; Gerco Den Hartog; Marien I. de Jonge; Ronald P. van Rij. 2020. "Berberine and obatoclax inhibit SARS-CoV-2 replication in primary human nasal epithelial cells in vitro." , no. : 1.

Research article
Published: 21 August 2020 in PLOS ONE
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Bordetella pertussis vaccine escape mutants that lack expression of the pertussis antigen pertactin (Prn) have emerged in vaccinated populations in the last 10–20 years. Additionally, clinical isolates lacking another acellular pertussis (aP) vaccine component, filamentous hemagglutinin (FHA), have been found sporadically. Here, we show that both whole-cell pertussis (wP) and aP vaccines induced protection in the lungs of mice, but that the wP vaccine was more effective in nasal clearance. Importantly, bacterial populations isolated from the lungs shifted to an FHA-negative phenotype due to frameshift mutations in the fhaB gene. Loss of FHA expression was strongly selected for in Prn-deficient strains in the lungs following aP but not wP vaccination. The combined loss of Prn and FHA led to complete abrogation of bacterial surface binding by aP-induced serum antibodies. This study demonstrates vaccine- and anatomical site-dependent adaptation of B. pertussis and has major implications for the design of improved pertussis vaccines.

ACS Style

Anne Zeddeman; Evi Van Schuppen; Kristianne E. Kok; Marjolein Van Gent; Kees J. Heuvelman; Marieke J. Bart; Han G. J. Van Der Heide; Joshua Gillard; Elles Simonetti; Marc J. Eleveld; Fred J. H. Van Opzeeland; Saskia Van Selm; Ronald De Groot; Marien I. De Jonge; Frits R. Mooi; Dimitri A. Diavatopoulos. Effect of FHA and Prn on Bordetella pertussis colonization of mice is dependent on vaccine type and anatomical site. PLOS ONE 2020, 15, e0237394 .

AMA Style

Anne Zeddeman, Evi Van Schuppen, Kristianne E. Kok, Marjolein Van Gent, Kees J. Heuvelman, Marieke J. Bart, Han G. J. Van Der Heide, Joshua Gillard, Elles Simonetti, Marc J. Eleveld, Fred J. H. Van Opzeeland, Saskia Van Selm, Ronald De Groot, Marien I. De Jonge, Frits R. Mooi, Dimitri A. Diavatopoulos. Effect of FHA and Prn on Bordetella pertussis colonization of mice is dependent on vaccine type and anatomical site. PLOS ONE. 2020; 15 (8):e0237394.

Chicago/Turabian Style

Anne Zeddeman; Evi Van Schuppen; Kristianne E. Kok; Marjolein Van Gent; Kees J. Heuvelman; Marieke J. Bart; Han G. J. Van Der Heide; Joshua Gillard; Elles Simonetti; Marc J. Eleveld; Fred J. H. Van Opzeeland; Saskia Van Selm; Ronald De Groot; Marien I. De Jonge; Frits R. Mooi; Dimitri A. Diavatopoulos. 2020. "Effect of FHA and Prn on Bordetella pertussis colonization of mice is dependent on vaccine type and anatomical site." PLOS ONE 15, no. 8: e0237394.

Other
Published: 24 April 2020
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SummaryColonization efficiency varies considerably between Streptococcus pneumoniae (pneumococcus) strains. The microbial characteristics that influence those differences are still largely unknown. Here, we report rates and kinetics of colonization of four pneumococcal strains upon experimental human pneumococcal challenge. Healthy adults were intranasally challenged with one of four pneumococcal strains (serotype/clonal name: 6B/BHN418, 15B/SH8286, 23F/P1121 and 23F/P833) over a range of doses. Maximum colonization achieved was 60%, 31%, 16% and 10%, respectively. Density and duration of colonization did not differ significantly between the tested strains. We further evaluated murine colonization, non-opsonic neutrophil mediated killing, epithelial cell adherence and average chain length of these four pneumococcal strains. Of these, only chain length was found to be associated with colonization efficiency in the human challenge model. Our data demonstrate that colonization rates following experimental challenge vary with the strain used and suggest that efficiency in colonization is related to pneumococcal chain length.

ACS Style

Sherin Pojar; Alan Basset; Jenna F. Gritzfeld; Elissavet Nikolaou; Saskia Van Selm; Marc J. Eleveld; Rebecca A. Gladstone; Carla Solórzano; Ankur B. Dalia; Esther German; Elena Mitsi; Victoria Connor; Angela D. Hyder-Wright; Helen Hill; Caz Hales; Tao Chen; Andrew Camilli; Andrea M. Collins; Jamie Rylance; Stephen D. Bentley; Simon P. Jochems; Marien I. De Jonge; Jeffrey N. Weiser; David W. Cleary; Stuart Clarke; Richard Malley; Stephen B. Gordon; Daniela M. Ferreira. Isolate differences in colonization efficiency during experimental human pneumococcal challenge. 2020, 1 .

AMA Style

Sherin Pojar, Alan Basset, Jenna F. Gritzfeld, Elissavet Nikolaou, Saskia Van Selm, Marc J. Eleveld, Rebecca A. Gladstone, Carla Solórzano, Ankur B. Dalia, Esther German, Elena Mitsi, Victoria Connor, Angela D. Hyder-Wright, Helen Hill, Caz Hales, Tao Chen, Andrew Camilli, Andrea M. Collins, Jamie Rylance, Stephen D. Bentley, Simon P. Jochems, Marien I. De Jonge, Jeffrey N. Weiser, David W. Cleary, Stuart Clarke, Richard Malley, Stephen B. Gordon, Daniela M. Ferreira. Isolate differences in colonization efficiency during experimental human pneumococcal challenge. . 2020; ():1.

Chicago/Turabian Style

Sherin Pojar; Alan Basset; Jenna F. Gritzfeld; Elissavet Nikolaou; Saskia Van Selm; Marc J. Eleveld; Rebecca A. Gladstone; Carla Solórzano; Ankur B. Dalia; Esther German; Elena Mitsi; Victoria Connor; Angela D. Hyder-Wright; Helen Hill; Caz Hales; Tao Chen; Andrew Camilli; Andrea M. Collins; Jamie Rylance; Stephen D. Bentley; Simon P. Jochems; Marien I. De Jonge; Jeffrey N. Weiser; David W. Cleary; Stuart Clarke; Richard Malley; Stephen B. Gordon; Daniela M. Ferreira. 2020. "Isolate differences in colonization efficiency during experimental human pneumococcal challenge." , no. : 1.