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

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.

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

10.1101/2020.08.18.255935 ◽

2020 ◽

Cited By ~ 9

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.

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

10.21203/rs.3.rs-128970/v1 ◽

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.

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

Cell Death and Disease ◽

10.1038/cddis.2017.372 ◽

2017 ◽

Vol 8 (8) ◽

pp. e2978-e2978 ◽

Cited By ~ 9

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

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

10.1101/2020.04.27.064279 ◽

2020 ◽

Cited By ~ 13

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.

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In vitro synthesis of DNA in nuclei isolated from human lung cells infected with herpes simplex type II virus.

Journal of Virology ◽

10.1128/jvi.15.2.322-331.1975 ◽

1975 ◽

Vol 15 (2) ◽

pp. 322-331 ◽

Cited By ~ 17

Author(s):

A R Kolber

Keyword(s):

Herpes Simplex ◽

Human Lung ◽

Herpes Simplex Type ◽

Lung Cells ◽

Type Ii ◽

In Vitro Synthesis ◽

Human Lung Cells

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Polyphosphate Reverses the Toxicity of the Quasi-Enzyme Bleomycin on Alveolar Endothelial Lung Cells In Vitro

Cancers ◽

10.3390/cancers13040750 ◽

2021 ◽

Vol 13 (4) ◽

pp. 750

Author(s):

Werner E. G. Müller ◽

Meik Neufurth ◽

Shunfeng Wang ◽

Heinz C. Schröder ◽

Xiaohong Wang

Keyword(s):

Dna Damage ◽

Human Lung ◽

Dna Integrity ◽

Lung Cells ◽

Antitumor Antibiotic ◽

Cell Toxicity ◽

Inorganic Polyphosphate ◽

Human Lung Cells ◽

Anti Cancer

The anti-cancer antitumor antibiotic bleomycin(s) (BLM) induces athyminic sites in DNA after its activation, a process that results in strand splitting. Here, using A549 human lung cells or BEAS-2B cells lunc cells, we show that the cell toxicity of BLM can be suppressed by addition of inorganic polyphosphate (polyP), a physiological polymer that accumulates and is released from platelets. BLM at a concentration of 20 µg ml−1 causes a decrease in cell viability (by ~70%), accompanied by an increased DNA damage and chromatin expansion (by amazingly 6-fold). Importantly, the BLM-caused effects on cell growth and DNA integrity are substantially suppressed by polyP. In parallel, the enlargement of the nuclei/chromatin in BLM-treated cells (diameter, 20–25 µm) is normalized to ~12 µm after co-incubation of the cells with BLM and polyP. A sequential application of the drugs (BLM for 3 days, followed by an exposure to polyP) does not cause this normalization. During co-incubation of BLM with polyP the gene for the BLM hydrolase is upregulated. It is concluded that by upregulating this enzyme polyP prevents the toxic side effects of BLM. These data might also contribute to an application of BLM in COVID-19 patients, since polyP inhibits binding of SARS-CoV-2 to cellular ACE2.

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

Nature Communications ◽

10.1038/s41467-021-24342-y ◽

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.

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