scholarly journals IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition

2020 ◽  
Author(s):  
Caterina Prelli Bozzo ◽  
Rayhane Nchioua ◽  
Meta Volcic ◽  
Jana Krüger ◽  
Sandra Heller ◽  
...  
Keyword(s):  
Viral Entry ◽  
Human Lung ◽  
Transmembrane Proteins ◽  
Cell Types ◽  
Lung Cells ◽  
Therapeutic Approaches ◽  
Viral Pathogens ◽  
Virus Inhibition ◽  
Human Lung Cells

Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) are thought to restrict numerous viral pathogens including severe acute respiratory syndrome coronaviruses (SARS-CoVs). However, most evidence comes from single-round pseudovirus infection studies of cells that overexpress IFITMs. Here, we verified that artificial overexpression of IFITMs blocks SARS-CoV-2 infection. Strikingly, however, endogenous IFITM expression was essential for efficient infection of genuine SARS-CoV-2 in human lung cells. Our results indicate that the SARS-CoV-2 Spike protein interacts with IFITMs and hijacks them for efficient viral entry. IFITM proteins were expressed and further induced by interferons in human lung, gut, heart and brain cells. Intriguingly, IFITM-derived peptides and targeting antibodies inhibited SARS-CoV-2 entry and replication in human lung cells, cardiomyocytes and gut organoids. Our results show that IFITM proteins are important cofactors for SARS-CoV-2 infection of human cell types representing in vivo targets for viral transmission, dissemination and pathogenesis and suitable targets for therapeutic approaches.

IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition

2021 ◽  
Author(s):  
Caterina Prelli Bozzo ◽  
Rayhane Nchioua ◽  
Meta Volcic ◽  
Jana Krüger ◽  
Sandra Heller ◽  
...  
Keyword(s):  
Viral Entry ◽  
Human Lung ◽  
Transmembrane Proteins ◽  
Cell Types ◽  
Lung Cells ◽  
Therapeutic Approaches ◽  
Viral Pathogens ◽  
Virus Inhibition ◽  
Human Lung Cells

Abstract Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) are thought to restrict numerous viral pathogens including severe acute respiratory syndrome coronaviruses (SARS-CoVs). However, most evidence comes from single-round pseudovirus infection studies of cells that overexpress IFITMs. Here, we verified that artificial overexpression of IFITMs blocks SARS-CoV-2 infection. Strikingly, however, endogenous IFITM expression was essential for efficient infection of genuine SARS-CoV-2 in human lung cells. Our results indicate that the SARS-CoV-2 Spike protein interacts with IFITMs and hijacks them for efficient viral entry. IFITM proteins were expressed and further induced by interferons in human lung, gut, heart and brain cells. Intriguingly, IFITM-derived peptides and targeting antibodies inhibited SARS-CoV-2 entry and replication in human lung cells, cardiomyocytes and gut organoids. Our results show that IFITM proteins are important cofactors for SARS-CoV-2 infection of human cell types representing in vivo targets for viral transmission, dissemination and pathogenesis and suitable targets for therapeutic approaches.

scholarly journals IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition in vitro

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Caterina Prelli Bozzo ◽  
Rayhane Nchioua ◽  
Meta Volcic ◽  
Lennart Koepke ◽  
Jana Krüger ◽  
...  
Keyword(s):  
Human Lung ◽  
Transmembrane Proteins ◽  
Cell Types ◽  
Lung Cells ◽  
Therapeutic Approaches ◽  
Viral Pathogens ◽  
Virus Inhibition ◽  
Human Lung Cells

AbstractInterferon-induced transmembrane proteins (IFITMs 1, 2 and 3) can restrict viral pathogens, but pro- and anti-viral activities have been reported for coronaviruses. Here, we show that artificial overexpression of IFITMs blocks SARS-CoV-2 infection. However, endogenous IFITM expression supports efficient infection of SARS-CoV-2 in human lung cells. Our results indicate that the SARS-CoV-2 Spike protein interacts with IFITMs and hijacks them for efficient viral infection. IFITM proteins were expressed and further induced by interferons in human lung, gut, heart and brain cells. IFITM-derived peptides and targeting antibodies inhibit SARS-CoV-2 entry and replication in human lung cells, cardiomyocytes and gut organoids. Our results show that IFITM proteins are cofactors for efficient SARS-CoV-2 infection of human cell types representing in vivo targets for viral transmission, dissemination and pathogenesis and are potential targets for therapeutic approaches.

scholarly journals Enzalutamide, a prostate cancer therapeutic, downregulates TMPRSS2 in lung and reduces cellular entry of SARS-CoV-2

2021 ◽  
Author(s):  
D. A. Leach ◽  
A. Mohr ◽  
E. S. Giotis ◽  
A. M. Isac ◽  
L. L. Yates ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Viral Entry ◽  
Human Lung ◽  
Therapeutic Potential ◽  
Cell Types ◽  
Surface Proteins ◽  
Lung Cells ◽  
Human Lung Cells ◽  
Transcription Factor Activation

Abstract The COVID-19 pandemic, caused by the novel human coronavirus SARS-CoV-2 coronavirus, attacks various organs but most destructively the lung. It has been shown that SARS-CoV-2 entry into lung cells requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; activation of the androgen receptor increases TMPRSS2 levels in various tissues, most notably the prostate. We show here that treatment with the antiandrogen enzalutamide – a well-tolerated drug widely used in advanced prostate cancer – reduces TMPRSS2 levels in human lung cells. Further, enzalutamide treatment of mice dramatically decreased Tmprss2 levels in the lung. To determine therapeutic potential, we assessed uptake of SARS-CoV-2 Spike protein pseudotyped lentivirus and live SARS-CoV-2 into human lung cells and saw a significant reduction in viral entry and infection upon treatment with the antiandrogens enzalutamide and bicalutamide. In support of this new experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types that are targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.

scholarly journals The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
D. A. Leach ◽  
A. Mohr ◽  
E. S. Giotis ◽  
E. Cil ◽  
A. M. Isac ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Human Lung ◽  
Cell Types ◽  
Receptor Activation ◽  
Surface Proteins ◽  
Mouse Lung ◽  
Lung Cells ◽  
Human Lung Cells ◽  
Cellular Entry ◽  
Experimental Data Analysis

AbstractSARS-CoV-2 attacks various organs, most destructively the lung, and cellular entry requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; androgen receptor activation increases TMPRSS2 levels in various tissues, most notably prostate. We show here that treatment with the antiandrogen enzalutamide—a well-tolerated drug widely used in advanced prostate cancer—reduces TMPRSS2 levels in human lung cells and in mouse lung. Importantly, antiandrogens significantly reduced SARS-CoV-2 entry and infection in lung cells. In support of this experimental data, analysis of existing datasets shows striking co-expression of AR and TMPRSS2, including in specific lung cell types targeted by SARS-CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.

scholarly journals Synergistic inhibition of SARS-CoV-2 cell entry by otamixaban and covalent protease inhibitors: pre-clinical assessment of pharmacological and molecular properties

2021 ◽  
Vol 12 (38) ◽  
pp. 12600-12609
Author(s):  
Tim Hempel ◽  
Katarina Elez ◽  
Nadine Krüger ◽  
Lluís Raich ◽  
Jonathan H. Shrimp ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Viral Entry ◽  
Clinical Assessment ◽  
Human Lung ◽  
Cell Entry ◽  
Lung Cells ◽  
Host Proteins ◽  
Synergistic Inhibition ◽  
Human Lung Cells

SARS-CoV-2, the cause of the COVID-19 pandemic, exploits host proteins for viral entry into human lung cells and is blocked by otamixaban in combination with a covalent protease inhibitor.

scholarly journals Rho inhibition by lovastatin affects apoptosis and DSB repair of primary human lung cells in vitro and lung tissue in vivo following fractionated irradiation

2017 ◽  
Vol 8 (8) ◽  
pp. e2978-e2978 ◽  
Author(s):  
Verena Ziegler ◽  
Christian Henninger ◽  
Ioannis Simiantonakis ◽  
Marcel Buchholzer ◽  
Mohammad Reza Ahmadian ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Human Lung ◽  
Lung Cells ◽  
Fractionated Irradiation ◽  
Dsb Repair ◽  
Human Lung Cells

scholarly journals TMPRSS2, required for SARS-CoV-2 entry, is downregulated in lung cells by enzalutamide, a prostate cancer therapeutic

2020 ◽  
Author(s):  
Damien A. Leach ◽  
Ana-Maria Isac ◽  
Charlotte L. Bevan ◽  
Greg N. Brooke
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Human Lung ◽  
Cell Types ◽  
Surface Proteins ◽  
Lung Cells ◽  
Human Lung Cells ◽  
Transcription Factor Activation ◽  
Host Cell Surface ◽  
Experimental Data Analysis

Abstract The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, attacks various organs but most destructively the lung. It has been shown that SARS-CoV-2 entry into lung cells requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; activation of the androgen receptor increases TMPRSS2 levels in various tissues, most notably the prostate. We show here that treatment with the antiandrogen enzalutamide – a well-tolerated drug widely used in advanced prostate cancer – reduces TMPRSS2 levels in human lung cells. Further, enzalutamide treatment of mice dramatically decreased Tmprss2 levels in the lung. In support of this new experimental data, analysis of existing datasets shows striking co- expression of AR and TMPRSS2, including in specific lung cell types that are targeted by SARS- CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.

scholarly journals Remdesivir potently inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice

2020 ◽  
Author(s):  
Andrea J. Pruijssers ◽  
Amelia S. George ◽  
Alexandra Schäfer ◽  
Sarah R. Leist ◽  
Lisa E. Gralinksi ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Human Lung ◽  
Viral Disease ◽  
Lung Cells ◽  
Airway Epithelial ◽  
Human Lung Cells ◽  
Epithelial Cultures ◽  
Viral Target

SUMMARYSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 as the causative agent of the novel pandemic viral disease COVID-19. With no approved therapies, this pandemic illustrates the urgent need for safe, broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV), a monophosphoramidate prodrug of an adenosine analog, potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 μM). Weaker activity was observed in Vero E6 cells (EC50 = 1.65 μM) due to their low capacity to metabolize RDV. To rapidly evaluate in vivo efficacy, we engineered a chimeric SARS-CoV encoding the viral target of RDV, the RNA-dependent RNA polymerase, of SARS-CoV-2. In mice infected with chimeric virus, therapeutic RDV administration diminished lung viral load and improved pulmonary function as compared to vehicle treated animals. These data provide evidence that RDV is potently active against SARS-CoV-2 in vitro and in vivo, supporting its further clinical testing for treatment of COVID-19.

scholarly journals Oxidative stress and inflammation response after nanoparticle exposure: differences between human lung cell monocultures and an advanced three-dimensional model of the human epithelial airways

2009 ◽  
Vol 7 (suppl_1) ◽  
Author(s):  
Loretta Müller ◽  
Michael Riediker ◽  
Peter Wick ◽  
Martin Mohr ◽  
Peter Gehr ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Cultures ◽  
Human Lung ◽  
Inflammatory Responses ◽  
Cell Types ◽  
Lung Cells ◽  
Cell Type ◽  
Human Lung Cells ◽  
Tnf Α ◽  
Triple Cell

Combustion-derived and manufactured nanoparticles (NPs) are known to provoke oxidative stress and inflammatory responses in human lung cells; therefore, they play an important role during the development of adverse health effects. As the lungs are composed of more than 40 different cell types, it is of particular interest to perform toxicological studies with co-cultures systems, rather than with monocultures of only one cell type, to gain a better understanding of complex cellular reactions upon exposure to toxic substances. Monocultures of A549 human epithelial lung cells, human monocyte-derived macrophages and monocyte-derived dendritic cells (MDDCs) as well as triple cell co-cultures consisting of all three cell types were exposed to combustion-derived NPs (diesel exhaust particles) and to manufactured NPs (titanium dioxide and single-walled carbon nanotubes). The penetration of particles into cells was analysed by transmission electron microscopy. The amount of intracellular reactive oxygen species (ROS), the total antioxidant capacity (TAC) and the production of tumour necrosis factor (TNF)-α and interleukin (IL)-8 were quantified. The results of the monocultures were summed with an adjustment for the number of each single cell type in the triple cell co-culture. All three particle types were found in all cell and culture types. The production of ROS was induced by all particle types in all cell cultures except in monocultures of MDDCs. The TAC and the (pro-)inflammatory reactions were not statistically significantly increased by particle exposure in any of the cell cultures. Interestingly, in the triple cell co-cultures, the TAC and IL-8 concentrations were lower and the TNF-α concentrations were higher than the expected values calculated from the monocultures. The interplay of different lung cell types seems to substantially modulate the oxidative stress and the inflammatory responses after NP exposure.

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