LIVIVO - The Search Portal for Life Sciences

zur deutschen Oberfläche wechseln
Advanced search

Search results

Result 1 - 10 of total 34

Search options

  1. Article: Characterization of Live-Attenuated Powassan Virus Vaccine Candidates Identifies an Efficacious Prime-Boost Strategy for Mitigating Powassan Virus Disease in a Murine Model.

    Cheung, Andrew M / Yip, Elaine Z / Ashbrook, Alison W / Goonawardane, Niluka / Quirk, Corrine / Rice, Charles M / MacDonald, Margaret R / Hoffmann, Hans-Heinrich

    Vaccines

    2023  Volume 11, Issue 3

    Abstract: Powassan virus (POWV) is an emerging tick-borne virus and cause of lethal encephalitis in humans. The lack of treatment or prevention strategies for POWV disease underscores the need for an effective POWV vaccine. Here, we took two independent approaches ...

    Abstract Powassan virus (POWV) is an emerging tick-borne virus and cause of lethal encephalitis in humans. The lack of treatment or prevention strategies for POWV disease underscores the need for an effective POWV vaccine. Here, we took two independent approaches to develop vaccine candidates. First, we recoded the POWV genome to increase the dinucleotide frequencies of CpG and UpA to potentially attenuate the virus by raising its susceptibility to host innate immune factors, such as the zinc-finger antiviral protein (ZAP). Secondly, we took advantage of the live-attenuated yellow fever virus vaccine 17D strain (YFV-17D) as a vector to express the structural genes pre-membrane (prM) and envelope (E) of POWV. The chimeric YFV-17D-POWV vaccine candidate was further attenuated for in vivo application by removing an N-linked glycosylation site within the nonstructural protein (NS)1 of YFV-17D. This live-attenuated chimeric vaccine candidate significantly protected mice from POWV disease, conferring a 70% survival rate after lethal challenge when administered in a homologous two-dose regimen. Importantly, when given in a heterologous prime-boost vaccination scheme, in which vaccination with the initial chimeric virus was followed by a protein boost with the envelope protein domain III (EDIII), 100% of the mice were protected without showing any signs of morbidity. Combinations of this live-attenuated chimeric YFV-17D-POWV vaccine candidate with an EDIII protein boost warrant further studies for the development of an effective vaccine strategy for the prevention of POWV disease.
    Language English
    Publishing date 2023-03-08
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2703319-3
    ISSN 2076-393X
    ISSN 2076-393X
    DOI 10.3390/vaccines11030612
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  2. Article ; Online: Sindbis Macrodomain Poly-ADP-Ribose Hydrolase Activity Is Important for Viral RNA Synthesis.

    Aguilar, Eduardo G / Paniccia, Gabrielle / Adura, Carolina / Singer, Zakary S / Ashbrook, Alison W / Razooky, Brandon S / Rice, Charles M / MacDonald, Margaret R

    Journal of virology

    2022  Volume 96, Issue 7, Page(s) e0151621

    Abstract: ADP-ribosylation is a highly dynamic posttranslational modification frequently studied in stress response pathways with recent attention given to its role in response to viral infection. Notably, the alphaviruses encode catalytically active macrodomains ... ...

    Abstract ADP-ribosylation is a highly dynamic posttranslational modification frequently studied in stress response pathways with recent attention given to its role in response to viral infection. Notably, the alphaviruses encode catalytically active macrodomains capable of ADP-ribosylhydrolase (ARH) activities, implying a role in remodeling the cellular ADP-ribosylome. This report decouples mono- and poly-ARH contributions to macrodomain function using a newly engineered Sindbis virus (SINV) mutant with attenuated poly-ARH activity. Our findings indicate that viral poly-ARH activity is uniquely required for high titer replication in mammalian systems. Despite translating incoming genomic RNA as efficiently as WT virus, mutant viruses have a reduced capacity to establish productive infection, offering a more complete understanding of the kinetics and role of the alphavirus macrodomain with important implications for broader ADP-ribosyltransferase biology.
    MeSH term(s) Animals ; Coronavirus/genetics ; Hydrolases/metabolism ; Mammals/genetics ; Poly Adenosine Diphosphate Ribose/metabolism ; RNA, Viral/genetics ; Sindbis Virus/enzymology ; Sindbis Virus/genetics ; Virus Replication
    Chemical Substances RNA, Viral ; Poly Adenosine Diphosphate Ribose (26656-46-2) ; Hydrolases (EC 3.-)
    Language English
    Publishing date 2022-03-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/jvi.01516-21
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  3. Article: Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection.

    Lercher, Alexander / Cheong, Jin-Gyu / Jiang, Chenyang / Hoffmann, Hans-Heinrich / Ashbrook, Alison W / Yin, Yue S / Quirk, Corrine / DeGrace, Emma J / Chiriboga, Luis / Rosenberg, Brad R / Josefowicz, Steven Z / Rice, Charles M

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Pathogen encounter results in long-lasting epigenetic imprinting that shapes diseases caused by heterologous pathogens. The breadth of this innate immune memory is of particular interest in the context of respiratory pathogens with increased pandemic ... ...

    Abstract Pathogen encounter results in long-lasting epigenetic imprinting that shapes diseases caused by heterologous pathogens. The breadth of this innate immune memory is of particular interest in the context of respiratory pathogens with increased pandemic potential and wide-ranging impact on global health. Here, we investigated epigenetic imprinting across cell lineages in a disease relevant murine model of SARS-CoV-2 recovery. Past SARS-CoV-2 infection resulted in increased chromatin accessibility of type I interferon (IFN-I) related transcription factors in airway-resident macrophages. Mechanistically, establishment of this innate immune memory required viral pattern recognition and canonical IFN-I signaling and augmented secondary antiviral responses. Past SARS-CoV-2 infection ameliorated disease caused by the heterologous respiratory pathogen influenza A virus. Insights into innate immune memory and how it affects subsequent infections with heterologous pathogens to influence disease pathology could facilitate the development of broadly effective therapeutic strategies.
    Language English
    Publishing date 2023-11-27
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.11.24.568354
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  4. Article ; Online: Mutagenesis of S-Adenosyl-l-Methionine-Binding Residues in Coronavirus nsp14 N7-Methyltransferase Demonstrates Differing Requirements for Genome Translation and Resistance to Innate Immunity.

    Case, James Brett / Ashbrook, Alison W / Dermody, Terence S / Denison, Mark R

    Journal of virology

    2016  Volume 90, Issue 16, Page(s) 7248–7256

    Abstract: Unlabelled: Eukaryotic mRNAs possess a methylated 5'-guanosine cap that is required for RNA stability, efficient translation, and protection from cell-intrinsic defenses. Many viruses use 5' caps or other mechanisms to mimic a cap structure to limit ... ...

    Abstract Unlabelled: Eukaryotic mRNAs possess a methylated 5'-guanosine cap that is required for RNA stability, efficient translation, and protection from cell-intrinsic defenses. Many viruses use 5' caps or other mechanisms to mimic a cap structure to limit detection of viral RNAs by intracellular innate sensors and to direct efficient translation of viral proteins. The coronavirus (CoV) nonstructural protein 14 (nsp14) is a multifunctional protein with N7-methyltransferase (N7-MTase) activity. The highly conserved S-adenosyl-l-methionine (SAM)-binding residues of the DxG motif are required for nsp14 N7-MTase activity in vitro However, the requirement for CoV N7-MTase activity and the importance of the SAM-binding residues during viral replication have not been determined. Here, we engineered mutations in murine hepatitis virus (MHV) nsp14 N7-MTase at residues D330 and G332 and determined the effects of these mutations on viral replication, sensitivity to mutagen, inhibition by type I interferon (IFN), and translation efficiency. Virus encoding a G332A substitution in nsp14 displayed delayed replication kinetics and decreased peak titers relative to wild-type (WT) MHV. In addition, replication of nsp14 G332A virus was diminished following treatment of cells with IFN-β, and nsp14 G332A genomes were translated less efficiently both in vitro and during viral infection. In contrast, substitution of alanine at MHV nsp14 D330 did not affect viral replication, sensitivity to mutagen, or inhibition by IFN-β compared to WT MHV. Our results demonstrate that the conserved MHV N7-MTase SAM-binding-site residues are not required for MHV viability and suggest that the determinants of CoV N7-MTase activity differ in vitro and during virus infection.
    Importance: Human coronaviruses, most notably severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, cause severe and lethal human disease. Since specific antiviral therapies are not available for the treatment of human coronavirus infections, it is essential to understand the functions of conserved CoV proteins in viral replication. Here, we show that substitution of alanine at G332 in the N7-MTase domain of nsp14 impairs viral replication, enhances sensitivity to the innate immune response, and reduces viral RNA translation efficiency. Our data support the idea that coronavirus RNA capping could be targeted for development of antiviral therapeutics.
    MeSH term(s) Amino Acid Sequence ; Animals ; Antiviral Agents/pharmacology ; Brain Neoplasms/enzymology ; Brain Neoplasms/genetics ; Brain Neoplasms/immunology ; Brain Neoplasms/virology ; Cells, Cultured ; Coronavirus/enzymology ; DNA Mutational Analysis ; Genome, Viral/physiology ; Humans ; Immunity, Innate/immunology ; Immunomodulation ; Interferon-beta/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutagenesis ; Mutation/genetics ; Protein Biosynthesis ; RNA, Viral/genetics ; RNA, Viral/metabolism ; Real-Time Polymerase Chain Reaction ; S-Adenosylmethionine/chemistry ; S-Adenosylmethionine/metabolism ; Sequence Homology, Amino Acid ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism ; Virus Replication
    Chemical Substances Antiviral Agents ; RNA, Viral ; Viral Nonstructural Proteins ; nonstructural protein, coronavirus ; Interferon-beta (77238-31-4) ; S-Adenosylmethionine (7LP2MPO46S)
    Keywords covid19
    Language English
    Publishing date 2016-07-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.00542-16
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  5. Article ; Online: Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection.

    Lercher, Alexander / Cheong, Jin-Gyu / Jiang, Chenyang / Hoffmann, Hans-Heinrich / Ashbrook, Alison W / Yin, Yue S / Quirk, Corrine / DeGrace, Emma J / Chiriboga, Luis / Rosenberg, Brad R / Josefowicz, Steven Z / Rice, Charles M

    bioRxiv

    Abstract: Pathogen encounter results in long-lasting epigenetic imprinting that shapes diseases caused by heterologous pathogens. The breadth of this innate immune memory is of particular interest in the context of respiratory pathogens with increased pandemic ... ...

    Abstract Pathogen encounter results in long-lasting epigenetic imprinting that shapes diseases caused by heterologous pathogens. The breadth of this innate immune memory is of particular interest in the context of respiratory pathogens with increased pandemic potential and wide-ranging impact on global health. Here, we investigated epigenetic imprinting across cell lineages in a disease relevant murine model of SARS-CoV-2 recovery. Past SARS-CoV-2 infection resulted in increased chromatin accessibility of type I interferon (IFN-I) related transcription factors in airway-resident macrophages. Mechanistically, establishment of this innate immune memory required viral pattern recognition and canonical IFN-I signaling and augmented secondary antiviral responses. Past SARS-CoV-2 infection ameliorated disease caused by the heterologous respiratory pathogen influenza A virus. Insights into innate immune memory and how it affects subsequent infections with heterologous pathogens to influence disease pathology could facilitate the development of broadly effective therapeutic strategies.
    Keywords covid19
    Language English
    Publishing date 2023-11-27
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2023.11.24.568354
    Database COVID19

    Kategorien

  6. Article ; Online: Metabolites with SARS-CoV-2 Inhibitory Activity Identified from Human Microbiome Commensals.

    Piscotta, Frank J / Hoffmann, Hans-Heinrich / Choi, Young Joo / Small, Gabriel I / Ashbrook, Alison W / Koirala, Bimal / Campbell, Elizabeth A / Darst, Seth A / Rice, Charles M / Brady, Sean F

    mSphere

    2021  Volume 6, Issue 6, Page(s) e0071121

    Abstract: The COVID-19 pandemic has highlighted the need to identify additional antiviral small molecules to complement existing therapies. Although increasing evidence suggests that metabolites produced by the human microbiome have diverse biological activities, ... ...

    Abstract The COVID-19 pandemic has highlighted the need to identify additional antiviral small molecules to complement existing therapies. Although increasing evidence suggests that metabolites produced by the human microbiome have diverse biological activities, their antiviral properties remain poorly explored. Using a cell-based SARS-CoV-2 infection assay, we screened culture broth extracts from a collection of phylogenetically diverse human-associated bacteria for the production of small molecules with antiviral activity. Bioassay-guided fractionation uncovered three bacterial metabolites capable of inhibiting SARS-CoV-2 infection. This included the nucleoside analogue N
    MeSH term(s) Antiviral Agents/pharmacology ; Bacteria/chemistry ; Bacteria/classification ; Bacteria/growth & development ; Bacteria/metabolism ; Biological Assay ; Cell Line, Tumor ; Culture Media/chemistry ; Culture Media/pharmacology ; Humans ; Metabolic Networks and Pathways ; Microbiota/physiology ; Molecular Docking Simulation ; Protease Inhibitors/pharmacology ; Protein Binding ; SARS-CoV-2/drug effects ; Symbiosis/physiology
    Chemical Substances Antiviral Agents ; Culture Media ; Protease Inhibitors
    Language English
    Publishing date 2021-12-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2379-5042
    ISSN (online) 2379-5042
    DOI 10.1128/mSphere.00711-21
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  7. Article ; Online: IL-6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease.

    Park, Jiwoon / Zhao, Yuanyuan / Zhang, Fan / Zhang, Shaoyan / Kwong, Andrew C / Zhang, Yujie / Hoffmann, Hans-Heinrich / Bushweller, Leila / Wu, Xin / Ashbrook, Alison W / Stefanovic, Branko / Chen, Shuyang / Branch, Andrea D / Mason, Christopher E / Jung, Jae U / Rice, Charles M / Wu, Xianfang

    Journal of hepatology

    2022  Volume 78, Issue 1, Page(s) 45–56

    Abstract: Background & aims: A number of genetic polymorphisms have been associated with susceptibility to or protection against non-alcoholic fatty liver disease (NAFLD), but the underlying mechanisms remain unknown. Here, we focused on the rs738409 C>G single ... ...

    Abstract Background & aims: A number of genetic polymorphisms have been associated with susceptibility to or protection against non-alcoholic fatty liver disease (NAFLD), but the underlying mechanisms remain unknown. Here, we focused on the rs738409 C>G single nucleotide polymorphism (SNP), which produces the I148M variant of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and is strongly associated with NAFLD.
    Methods: To enable mechanistic dissection, we developed a human pluripotent stem cell (hPSC)-derived multicellular liver culture by incorporating hPSC-derived hepatocytes, hepatic stellate cells, and macrophages. We first applied this liver culture to model NAFLD by utilising a lipotoxic milieu reflecting the circulating levels of disease risk factors in affected individuals. We then created an isogenic pair of liver cultures differing only at rs738049 and compared NAFLD phenotype development.
    Results: Our hPSC-derived liver culture recapitulated many key characteristics of NAFLD development and progression including lipid accumulation and oxidative stress, inflammatory response, and stellate cell activation. Under the lipotoxic conditions, the I148M variant caused the enhanced development of NAFLD phenotypes. These differences were associated with elevated IL-6/signal transducer and activator of transcription 3 (STAT3) activity in liver cultures, consistent with transcriptomic data of liver biopsies from individuals carrying the rs738409 SNP. Dampening IL-6/STAT3 activity alleviated the I148M-mediated susceptibility to NAFLD, whereas boosting it in wild-type liver cultures enhanced NAFLD development. Finally, we attributed this elevated IL-6/STAT3 activity in liver cultures carrying the rs738409 SNP to increased NF-κB activity.
    Conclusions: Our study thus reveals a potential causal link between elevated IL-6/STAT3 activity and 148M-mediated susceptibility to NAFLD.
    Impact and implications: An increasing number of genetic variants manifest in non-alcoholic fatty liver disease (NAFLD) development and progression; however, the underlying mechanisms remain elusive. To study these variants in human-relevant systems, we developed an induced pluripotent stem cell-derived multicellular liver culture and focused on a common genetic variant (i.e. rs738409 in PNPLA3). Our findings not only provide mechanistic insight, but also a potential therapeutic strategy for NAFLD driven by this genetic variant in PNPLA3. Our liver culture is therefore a useful platform for exploring genetic variants in NAFLD development.
    MeSH term(s) Humans ; Genetic Predisposition to Disease ; Interleukin-6/genetics ; Interleukin-6/metabolism ; Liver/pathology ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Non-alcoholic Fatty Liver Disease/genetics ; Non-alcoholic Fatty Liver Disease/pathology ; Phospholipases A2, Calcium-Independent/genetics ; Polymorphism, Single Nucleotide ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism
    Chemical Substances Interleukin-6 ; Membrane Proteins ; Phospholipases A2, Calcium-Independent (EC 3.1.1.4) ; PNPLA3 protein, human (EC 3.1.1.3) ; STAT3 protein, human ; STAT3 Transcription Factor
    Language English
    Publishing date 2022-08-30
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 605953-3
    ISSN 1600-0641 ; 0168-8278
    ISSN (online) 1600-0641
    ISSN 0168-8278
    DOI 10.1016/j.jhep.2022.08.022
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  8. Article ; Online: Defining the proteolytic landscape during enterovirus infection.

    Saeed, Mohsan / Kapell, Sebastian / Hertz, Nicholas T / Wu, Xianfang / Bell, Kierstin / Ashbrook, Alison W / Mark, Milica Tesic / Zebroski, Henry A / Neal, Maxwell L / Flodström-Tullberg, Malin / MacDonald, Margaret R / Aitchison, John D / Molina, Henrik / Rice, Charles M

    PLoS pathogens

    2020  Volume 16, Issue 9, Page(s) e1008927

    Abstract: Viruses cleave cellular proteins to remodel the host proteome. The study of these cleavages has revealed mechanisms of immune evasion, resource exploitation, and pathogenesis. However, the full extent of virus-induced proteolysis in infected cells is ... ...

    Abstract Viruses cleave cellular proteins to remodel the host proteome. The study of these cleavages has revealed mechanisms of immune evasion, resource exploitation, and pathogenesis. However, the full extent of virus-induced proteolysis in infected cells is unknown, mainly because until recently the technology for a global view of proteolysis within cells was lacking. Here, we report the first comprehensive catalog of proteins cleaved upon enterovirus infection and identify the sites within proteins where the cleavages occur. We employed multiple strategies to confirm protein cleavages and assigned them to one of the two enteroviral proteases. Detailed characterization of one substrate, LSM14A, a p body protein with a role in antiviral immunity, showed that cleavage of this protein disrupts its antiviral function. This study yields a new depth of information about the host interface with a group of viruses that are both important biological tools and significant agents of disease.
    MeSH term(s) Antiviral Agents/metabolism ; Cysteine Endopeptidases/metabolism ; Enterovirus/metabolism ; Enterovirus/pathogenicity ; Enterovirus Infections/virology ; Host-Pathogen Interactions/physiology ; Humans ; Proteolysis ; Viral Proteins/metabolism ; Virus Replication/physiology
    Chemical Substances Antiviral Agents ; Viral Proteins ; Cysteine Endopeptidases (EC 3.4.22.-)
    Language English
    Publishing date 2020-09-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1008927
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  9. Article: Genome-scale identification of SARS-CoV-2 and pan-coronavirus host factor networks.

    Schneider, William M / Luna, Joseph M / Hoffmann, H-Heinrich / Sánchez-Rivera, Francisco J / Leal, Andrew A / Ashbrook, Alison W / Le Pen, Jérémie / Michailidis, Eleftherios / Ricardo-Lax, Inna / Peace, Avery / Stenzel, Ansgar F / Lowe, Scott W / MacDonald, Margaret R / Rice, Charles M / Poirier, John T

    bioRxiv : the preprint server for biology

    2020  

    Abstract: The COVID-19 pandemic has claimed the lives of more than one million people worldwide. The causative agent, SARS-CoV-2, is a member of the : Highlights: Genome-wide CRISPR screens for SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E coronavirus host ... ...

    Abstract The COVID-19 pandemic has claimed the lives of more than one million people worldwide. The causative agent, SARS-CoV-2, is a member of the
    Highlights: Genome-wide CRISPR screens for SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E coronavirus host factors.Parallel genome-wide CRISPR screening uncovered host factors and pathways with pan-coronavirus and virus-specific functional roles.Coronaviruses co-opt multiple biological pathways, including glycosaminoglycan biosynthesis, SREBP signaling, and glycosylphosphatidylinositol biosynthesis and anchoring, among others.TMEM41B - a poorly understood factor with roles in autophagy and lipid mobilization - is a critical pan-coronavirus host factor.
    Keywords covid19
    Language English
    Publishing date 2020-10-08
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2020.10.07.326462
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

  10. Article ; Online: Genome-Scale Identification of SARS-CoV-2 and Pan-coronavirus Host Factor Networks.

    Schneider, William M / Luna, Joseph M / Hoffmann, H-Heinrich / Sánchez-Rivera, Francisco J / Leal, Andrew A / Ashbrook, Alison W / Le Pen, Jérémie / Ricardo-Lax, Inna / Michailidis, Eleftherios / Peace, Avery / Stenzel, Ansgar F / Lowe, Scott W / MacDonald, Margaret R / Rice, Charles M / Poirier, John T

    Cell

    2020  Volume 184, Issue 1, Page(s) 120–132.e14

    Abstract: The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of over one million people worldwide. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a member of the Coronaviridae family of viruses that can ... ...

    Abstract The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of over one million people worldwide. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a member of the Coronaviridae family of viruses that can cause respiratory infections of varying severity. The cellular host factors and pathways co-opted during SARS-CoV-2 and related coronavirus life cycles remain ill defined. To address this gap, we performed genome-scale CRISPR knockout screens during infection by SARS-CoV-2 and three seasonal coronaviruses (HCoV-OC43, HCoV-NL63, and HCoV-229E). These screens uncovered host factors and pathways with pan-coronavirus and virus-specific functional roles, including major dependency on glycosaminoglycan biosynthesis, sterol regulatory element-binding protein (SREBP) signaling, bone morphogenetic protein (BMP) signaling, and glycosylphosphatidylinositol biosynthesis, as well as a requirement for several poorly characterized proteins. We identified an absolute requirement for the VMP1, TMEM41, and TMEM64 (VTT) domain-containing protein transmembrane protein 41B (TMEM41B) for infection by SARS-CoV-2 and three seasonal coronaviruses. This human coronavirus host factor compendium represents a rich resource to develop new therapeutic strategies for acute COVID-19 and potential future coronavirus pandemics.
    MeSH term(s) A549 Cells ; Cell Line ; Clustered Regularly Interspaced Short Palindromic Repeats ; Coronavirus 229E, Human/physiology ; Coronavirus Infections/genetics ; Coronavirus Infections/virology ; Coronavirus NL63, Human/physiology ; Coronavirus OC43, Human/physiology ; Gene Knockout Techniques ; Genome-Wide Association Study ; HEK293 Cells ; Host-Pathogen Interactions/drug effects ; Humans ; Membrane Proteins/metabolism ; Metabolic Networks and Pathways/drug effects ; Protein Interaction Mapping ; SARS-CoV-2/physiology
    Chemical Substances Membrane Proteins ; TMEM41B protein, human
    Language English
    Publishing date 2020-12-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2020.12.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

    More links

    Kategorien

To top