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  1. Article: Live imaging of the airway epithelium reveals that mucociliary clearance modulates SARS-CoV-2 spread.

    Hope, Thomas / Becker, Mark / Martin-Sancho, Laura / Simons, Lacy / McRaven, Michael / Chanda, Sumit / Hultquist, Judd

    Research square

    2023  

    Abstract: SARS-CoV-2 initiates infection in the conducting airways, which rely on mucocilliary clearance (MCC) to minimize pathogen penetration. However, it is unclear how MCC impacts SARS-CoV-2 spread after infection is established. To understand viral spread at ... ...

    Abstract SARS-CoV-2 initiates infection in the conducting airways, which rely on mucocilliary clearance (MCC) to minimize pathogen penetration. However, it is unclear how MCC impacts SARS-CoV-2 spread after infection is established. To understand viral spread at this site, we performed live imaging of SARS-CoV-2 infected differentiated primary human bronchial epithelium cultures for up to 9 days. Fluorescent markers for cilia and mucus allowed longitudinal monitoring of MCC, ciliary motion, and infection. The number of infected cells peaked at 4 days post-infection in characteristic foci that followed mucus movement. Inhibition of MCC using physical and genetic perturbations limited foci. Later in infection, MCC was diminished despite relatively subtle ciliary function defects. Resumption of MCC and infection spread after mucus removal suggests that mucus secretion mediates this effect. We show that MCC facilitates SARS-CoV-2 spread early in infection while later decreases in MCC inhibit spread, suggesting a complex interplay between SARS-CoV-2 and MCC.
    Language English
    Publishing date 2023-09-08
    Publishing country United States
    Document type Preprint
    DOI 10.21203/rs.3.rs-3246773/v1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Activation of the Interferon Pathway in Trophoblast Cells Productively Infected with SARS-CoV-2.

    Kallol, Sampada / Martin-Sancho, Laura / Morey, Robert / Aisagbonhi, Omonigho / Pizzo, Donald / Meads, Morgan / Chanda, Sumit K / Soncin, Francesca

    Stem cells and development

    2023  Volume 32, Issue 9-10, Page(s) 225–236

    Abstract: SARS-CoV-2 infection during pregnancy has been associated with poor maternal and neonatal outcomes and placental defects. The placenta, which acts as a physical and immunological barrier at the maternal-fetal interface, is not established until the end ... ...

    Abstract SARS-CoV-2 infection during pregnancy has been associated with poor maternal and neonatal outcomes and placental defects. The placenta, which acts as a physical and immunological barrier at the maternal-fetal interface, is not established until the end of the first trimester. Therefore, localized viral infection of the trophoblast compartment early in gestation could trigger an inflammatory response resulting in altered placental function and consequent suboptimal conditions for fetal growth and development. In this study, we investigated the effect of SARS-CoV-2 infection in early gestation placentae using placenta-derived human trophoblast stem cells (TSCs), a novel in vitro model, and their extravillous trophoblast (EVT) and syncytiotrophoblast (STB) derivatives. SARS-CoV-2 was able to productively replicate in TSC-derived STB and EVT, but not undifferentiated TSCs, which is consistent with the expression of SARS-CoV-2 entry host factors, ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane cellular serine protease) in these cells. In addition, both TSC-derived EVT and STB infected with SARS-CoV-2 elicited an interferon-mediated innate immune response. Combined, these results suggest that placenta-derived TSCs are a robust in vitro model to investigate the effect of SARS-CoV-2 infection in the trophoblast compartment of the early placenta and that SARS-CoV-2 infection in early gestation activates the innate immune response and inflammation pathways. Therefore, placental development could be adversely affected by early SARS-CoV-2 infection by directly infecting the developing differentiated trophoblast compartment, posing a higher risk for poor pregnancy outcomes.
    MeSH term(s) Infant, Newborn ; Pregnancy ; Female ; Humans ; SARS-CoV-2 ; COVID-19/metabolism ; Trophoblasts/metabolism ; Interferons ; Placenta
    Chemical Substances Interferons (9008-11-1)
    Language English
    Publishing date 2023-03-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2142214-X
    ISSN 1557-8534 ; 1547-3287
    ISSN (online) 1557-8534
    ISSN 1547-3287
    DOI 10.1089/scd.2022.0255
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Synthetic lethality-based prediction of anti-SARS-CoV-2 targets.

    Pal, Lipika R / Cheng, Kuoyuan / Nair, Nishanth Ulhas / Martin-Sancho, Laura / Sinha, Sanju / Pu, Yuan / Riva, Laura / Yin, Xin / Schischlik, Fiorella / Lee, Joo Sang / Chanda, Sumit K / Ruppin, Eytan

    iScience

    2022  Volume 25, Issue 5, Page(s) 104311

    Abstract: Novel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic lethal ... ...

    Abstract Novel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic lethal and synthetic dosage lethal (SL/SDL) partners of such altered host genes. Pursuing this disparate antiviral strategy, here we comprehensively analyzed multiple
    Language English
    Publishing date 2022-04-27
    Publishing country United States
    Document type Journal Article
    ISSN 2589-0042
    ISSN (online) 2589-0042
    DOI 10.1016/j.isci.2022.104311
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Rising to the challenge of COVID-19: Working on SARS-CoV-2 during the pandemic.

    Stern-Ginossar, Noam / Kanneganti, Thirumala-Devi / Cameron, Craig E / Lou, Zhiyong / Cherry, Sara / Abraham, Jonathan / Martin-Sancho, Laura

    Molecular cell

    2021  Volume 81, Issue 11, Page(s) 2261–2265

    Abstract: COVID-19 altered our lives and pushed scientific research to operate at breakneck speed, leading to significant breakthroughs in record time. We asked experts in the field about the challenges they faced in transitioning, rapidly but safely, to working ... ...

    Abstract COVID-19 altered our lives and pushed scientific research to operate at breakneck speed, leading to significant breakthroughs in record time. We asked experts in the field about the challenges they faced in transitioning, rapidly but safely, to working on the virus while navigating the shutdown. Their voices converge on the importance of teamwork, forging new collaborations, and working toward a shared goal.
    MeSH term(s) Biomedical Research ; COVID-19/epidemiology ; COVID-19/prevention & control ; Humans ; Pandemics ; Poetry as Topic ; Quarantine ; SARS-CoV-2
    Language English
    Publishing date 2021-06-04
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2021.05.021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: A BioID-Derived Proximity Interactome for SARS-CoV-2 Proteins.

    May, Danielle G / Martin-Sancho, Laura / Anschau, Valesca / Liu, Sophie / Chrisopulos, Rachel J / Scott, Kelsey L / Halfmann, Charles T / Díaz Peña, Ramon / Pratt, Dexter / Campos, Alexandre R / Roux, Kyle J

    Viruses

    2022  Volume 14, Issue 3

    Abstract: The novel coronavirus SARS-CoV-2 is responsible for the ongoing COVID-19 pandemic and has caused a major health and economic burden worldwide. Understanding how SARS-CoV-2 viral proteins behave in host cells can reveal underlying mechanisms of ... ...

    Abstract The novel coronavirus SARS-CoV-2 is responsible for the ongoing COVID-19 pandemic and has caused a major health and economic burden worldwide. Understanding how SARS-CoV-2 viral proteins behave in host cells can reveal underlying mechanisms of pathogenesis and assist in development of antiviral therapies. Here, the cellular impact of expressing SARS-CoV-2 viral proteins was studied by global proteomic analysis, and proximity biotinylation (BioID) was used to map the SARS-CoV-2 virus-host interactome in human lung cancer-derived cells. Functional enrichment analyses revealed previously reported and unreported cellular pathways that are associated with SARS-CoV-2 proteins. We have established a website to host the proteomic data to allow for public access and continued analysis of host-viral protein associations and whole-cell proteomes of cells expressing the viral-BioID fusion proteins. Furthermore, we identified 66 high-confidence interactions by comparing this study with previous reports, providing a strong foundation for future follow-up studies. Finally, we cross-referenced candidate interactors with the CLUE drug library to identify potential therapeutics for drug-repurposing efforts. Collectively, these studies provide a valuable resource to uncover novel SARS-CoV-2 biology and inform development of antivirals.
    MeSH term(s) Biotinylation ; COVID-19 ; Humans ; Pandemics ; Proteomics ; SARS-CoV-2
    Language English
    Publishing date 2022-03-15
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2516098-9
    ISSN 1999-4915 ; 1999-4915
    ISSN (online) 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v14030611
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Synthetic lethality-based prediction of anti-SARS-CoV-2 targets.

    Pal, Lipika R / Cheng, Kuoyuan / Nair, Nishanth Ulhas / Martin-Sancho, Laura / Sinha, Sanju / Pu, Yuan / Riva, Laura / Yin, Xin / Schischlik, Fiorella / Lee, Joo Sang / Chanda, Sumit K / Ruppin, Eytan

    bioRxiv : the preprint server for biology

    2021  

    Abstract: Novel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic lethal ( ... ...

    Abstract Novel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic lethal (SL) partners of such altered host genes. Pursuing this antiviral strategy, here we comprehensively analyzed multiple
    Language English
    Publishing date 2021-09-15
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2021.09.14.460408
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Genome-scale metabolic modeling reveals SARS-CoV-2-induced metabolic changes and antiviral targets.

    Cheng, Kuoyuan / Martin-Sancho, Laura / Pal, Lipika R / Pu, Yuan / Riva, Laura / Yin, Xin / Sinha, Sanju / Nair, Nishanth Ulhas / Chanda, Sumit K / Ruppin, Eytan

    bioRxiv : the preprint server for biology

    2021  

    Abstract: Tremendous progress has been made to control the COVID-19 pandemic caused by the SARS-CoV-2 virus. However, effective therapeutic options are still rare. Drug repurposing and combination represent practical strategies to address this urgent unmet medical ...

    Abstract Tremendous progress has been made to control the COVID-19 pandemic caused by the SARS-CoV-2 virus. However, effective therapeutic options are still rare. Drug repurposing and combination represent practical strategies to address this urgent unmet medical need. Viruses, including coronaviruses, are known to hijack host metabolism to facilitate viral proliferation, making targeting host metabolism a promising antiviral approach. Here, we describe an integrated analysis of 12 published
    Language English
    Publishing date 2021-08-25
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2021.01.27.428543
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Genome-scale metabolic modeling reveals SARS-CoV-2-induced metabolic changes and antiviral targets.

    Cheng, Kuoyuan / Martin-Sancho, Laura / Pal, Lipika R / Pu, Yuan / Riva, Laura / Yin, Xin / Sinha, Sanju / Nair, Nishanth Ulhas / Chanda, Sumit K / Ruppin, Eytan

    Molecular systems biology

    2021  Volume 17, Issue 11, Page(s) e10260

    Abstract: Tremendous progress has been made to control the COVID-19 pandemic caused by the SARS-CoV-2 virus. However, effective therapeutic options are still rare. Drug repurposing and combination represent practical strategies to address this urgent unmet medical ...

    Abstract Tremendous progress has been made to control the COVID-19 pandemic caused by the SARS-CoV-2 virus. However, effective therapeutic options are still rare. Drug repurposing and combination represent practical strategies to address this urgent unmet medical need. Viruses, including coronaviruses, are known to hijack host metabolism to facilitate viral proliferation, making targeting host metabolism a promising antiviral approach. Here, we describe an integrated analysis of 12 published in vitro and human patient gene expression datasets on SARS-CoV-2 infection using genome-scale metabolic modeling (GEM), revealing complicated host metabolism reprogramming during SARS-CoV-2 infection. We next applied the GEM-based metabolic transformation algorithm to predict anti-SARS-CoV-2 targets that counteract the virus-induced metabolic changes. We successfully validated these targets using published drug and genetic screen data and by performing an siRNA assay in Caco-2 cells. Further generating and analyzing RNA-sequencing data of remdesivir-treated Vero E6 cell samples, we predicted metabolic targets acting in combination with remdesivir, an approved anti-SARS-CoV-2 drug. Our study provides clinical data-supported candidate anti-SARS-CoV-2 targets for future evaluation, demonstrating host metabolism targeting as a promising antiviral strategy.
    MeSH term(s) Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/therapeutic use ; Alanine/analogs & derivatives ; Alanine/therapeutic use ; Animals ; Antiviral Agents/therapeutic use ; COVID-19/metabolism ; COVID-19/virology ; Caco-2 Cells ; Chlorocebus aethiops ; Datasets as Topic ; Drug Development ; Drug Repositioning ; Host-Pathogen Interactions ; Humans ; Metabolic Networks and Pathways/genetics ; Pandemics ; RNA, Small Interfering ; SARS-CoV-2/physiology ; Sequence Analysis, RNA ; Vero Cells ; COVID-19 Drug Treatment
    Chemical Substances Antiviral Agents ; RNA, Small Interfering ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Alanine (OF5P57N2ZX)
    Language English
    Publishing date 2021-10-28
    Publishing country England
    Document type Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2193510-5
    ISSN 1744-4292 ; 1744-4292
    ISSN (online) 1744-4292
    ISSN 1744-4292
    DOI 10.15252/msb.202110260
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Genome-scale metabolic modeling reveals SARS-CoV-2-induced host metabolic reprogramming and identifies metabolic antiviral targets

    Cheng, Kuoyuan / Riva, Laura / Sinha, Sanju / Pal, Lipika Ray / Nair, Nishanth Ulhas / Martin-Sancho, Laura / Chanda, Sumit K. / Ruppin, Eytan

    bioRxiv

    Abstract: Tremendous progress has been made to control the COVID-19 pandemic, including the development and approval of vaccines as well as the drug remdesivir, which inhibits the SARS-CoV-2 virus that causes COVID-19. However, remdesivir confers only mild ... ...

    Abstract Tremendous progress has been made to control the COVID-19 pandemic, including the development and approval of vaccines as well as the drug remdesivir, which inhibits the SARS-CoV-2 virus that causes COVID-19. However, remdesivir confers only mild benefits to a subset of patients, and additional effective therapeutic options are needed. Drug repurposing and drug combinations may represent practical strategies to address these urgent unmet medical needs. Viruses, including coronaviruses, are known to hijack the host metabolism to facilitate their own proliferation, making targeting host metabolism a promising antiviral approach. Here, we describe an integrated analysis of 12 published in vitro and human patient gene expression datasets on SARS-CoV-2 infection using genome-scale metabolic modeling (GEM). We find that SARS-CoV-2 infection can induce recurrent and complicated metabolic reprogramming spanning a wide range of metabolic pathways. We next applied the GEM-based metabolic transformation algorithm (MTA) to predict anti-SARS-CoV-2 targets that counteract the virus-induced metabolic changes. These predictions are enriched for validated targets from various published experimental drug and genetic screens. Further analyzing the RNA-sequencing data of remdesivir-treated Vero E6 cell samples that we generated, we predicted metabolic targets that act in combination with remdesivir. These predictions are enriched for previously reported synergistic drugs with remdesivir. Since our predictions are based in part on human patient data, they are likely to be clinically relevant. We provide our top high-confidence candidate targets for their evaluation in further studies, demonstrating host metabolism-targeting as a promising antiviral strategy.
    Keywords covid19
    Language English
    Publishing date 2021-01-28
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2021.01.27.428543
    Database COVID19

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  10. Article ; Online: Synthetic lethality-based prediction of anti-SARS-CoV-2 targets

    Lipika R. Pal / Kuoyuan Cheng / Nishanth Ulhas Nair / Laura Martin-Sancho / Sanju Sinha / Yuan Pu / Laura Riva / Xin Yin / Fiorella Schischlik / Joo Sang Lee / Sumit K. Chanda / Eytan Ruppin

    iScience, Vol 25, Iss 5, Pp 104311- (2022)

    2022  

    Abstract: Summary: Novel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic ...

    Abstract Summary: Novel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic lethal and synthetic dosage lethal (SL/SDL) partners of such altered host genes. Pursuing this disparate antiviral strategy, here we comprehensively analyzed multiple in vitro and in vivo bulk and single-cell RNA-sequencing datasets of SARS-CoV-2 infection to predict clinically relevant candidate antiviral targets that are SL/SDL with altered host genes. The predicted SL/SDL-based targets are highly enriched for infected cell inhibiting genes reported in four SARS-CoV-2 CRISPR-Cas9 genome-wide genetic screens. We further selected a focused subset of 26 genes that we experimentally tested in a targeted siRNA screen using human Caco-2 cells. Notably, as predicted, knocking down these targets reduced viral replication and cell viability only under the infected condition without harming noninfected healthy cells.
    Keywords Drugs ; Virology ; Synthetic biology ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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