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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.
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 StyleFinny 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 StyleFinny 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.
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.
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 StyleFinny 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 StyleFinny 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.
Neutrophils are critical to the generation of effective immune responses and for killing invading microbes. Paired immune receptors provide important mechanisms to modulate neutrophil activation thresholds and effector functions. Expression of the leukocyte Ig-like receptor (LILR)A6 (ILT8/CD85b) and LILRB3 (ILT5/CD85a) paired-receptor system on human neutrophils has remained unclear because of the lack of specific molecular tools. Additionally, there is little known of their possible functions in neutrophil biology. The objective of this study was to characterize expression of LILRA6/LILRB3 receptors during human neutrophil differentiation and activation, and to assess their roles in modulating Fc receptor–mediated effector functions. LILRB3, but not LILRA6, was detected in human neutrophil lysates following immunoprecipitation by mass spectrometry. We demonstrate high LILRB3 expression on the surface of resting neutrophils and release from the surface following neutrophil activation. Surface expression was recapitulated in a human PLB-985 cell model of neutrophil-like differentiation. Continuous ligation of LILRB3 inhibited key IgA-mediated effector functions, including production of reactive oxygen species, phagocytic uptake, and microbial killing. This suggests that LILRB3 provides an important checkpoint to control human neutrophil activation and their antimicrobial effector functions during resting and early-activation stages of the neutrophil life cycle.
Yuxi Zhao; Esther Van Woudenbergh; Jing Zhu; Albert J. R. Heck; Kok P. M. Van Kessel; Carla J. C. De Haas; Piet C. Aerts; Jos A. G. Van Strijp; Alex J. McCarthy. The Orphan Immune Receptor LILRB3 Modulates Fc Receptor–Mediated Functions of Neutrophils. The Journal of Immunology 2020, 204, 954 -966.
AMA StyleYuxi Zhao, Esther Van Woudenbergh, Jing Zhu, Albert J. R. Heck, Kok P. M. Van Kessel, Carla J. C. De Haas, Piet C. Aerts, Jos A. G. Van Strijp, Alex J. McCarthy. The Orphan Immune Receptor LILRB3 Modulates Fc Receptor–Mediated Functions of Neutrophils. The Journal of Immunology. 2020; 204 (4):954-966.
Chicago/Turabian StyleYuxi Zhao; Esther Van Woudenbergh; Jing Zhu; Albert J. R. Heck; Kok P. M. Van Kessel; Carla J. C. De Haas; Piet C. Aerts; Jos A. G. Van Strijp; Alex J. McCarthy. 2020. "The Orphan Immune Receptor LILRB3 Modulates Fc Receptor–Mediated Functions of Neutrophils." The Journal of Immunology 204, no. 4: 954-966.
Cathelicidins are host defense peptides with antimicrobial and immunomodulatory functions. These effector molecules of the innate immune system of many vertebrates are diverse in their amino acid sequence but share physicochemical characteristics like positive charge and amphipathicity. Besides being antimicrobial, cathelicidins have a wide variety in immunomodulatory functions, both boosting and inhibiting inflammation, directing chemotaxis, and effecting cell differentiation, primarily towards type 1 immune responses. In this review, we will examine the biology and various functions of cathelicidins, focusing on putting in vitro results in the context of in vivo situations. The pro-inflammatory and anti-inflammatory functions are highlighted, as well both direct and indirect effects on chemotaxis and cell differentiation. Additionally, we will discuss the potential and limitations of using cathelicidins as immunomodulatory or antimicrobial drugs.
Roel M. Van Harten; Esther van Woudenbergh; Albert Van Dijk; Henk P. Haagsman. Cathelicidins: Immunomodulatory Antimicrobials. Vaccines 2018, 6, 63 .
AMA StyleRoel M. Van Harten, Esther van Woudenbergh, Albert Van Dijk, Henk P. Haagsman. Cathelicidins: Immunomodulatory Antimicrobials. Vaccines. 2018; 6 (3):63.
Chicago/Turabian StyleRoel M. Van Harten; Esther van Woudenbergh; Albert Van Dijk; Henk P. Haagsman. 2018. "Cathelicidins: Immunomodulatory Antimicrobials." Vaccines 6, no. 3: 63.