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  1. Article ; Online: Common human genetic variants of APOE impact murine COVID-19 mortality.

    Ostendorf, Benjamin N / Patel, Mira A / Bilanovic, Jana / Hoffmann, H-Heinrich / Carrasco, Sebastian E / Rice, Charles M / Tavazoie, Sohail F

    Nature

    2022  Volume 611, Issue 7935, Page(s) 346–351

    Abstract: Clinical outcomes of severe acute respiratory syndrome 2 (SARS-CoV-2) infection are highly heterogeneous, ranging from asymptomatic infection to lethal coronavirus disease 2019 (COVID-19). The factors underlying this heterogeneity remain insufficiently ... ...

    Abstract Clinical outcomes of severe acute respiratory syndrome 2 (SARS-CoV-2) infection are highly heterogeneous, ranging from asymptomatic infection to lethal coronavirus disease 2019 (COVID-19). The factors underlying this heterogeneity remain insufficiently understood. Genetic association studies have suggested that genetic variants contribute to the heterogeneity of COVID-19 outcomes, but the underlying potential causal mechanisms are insufficiently understood. Here we show that common variants of the apolipoprotein E (APOE) gene, homozygous in approximately 3% of the world's population
    MeSH term(s) Animals ; Humans ; Male ; Mice ; Apolipoprotein E2/genetics ; Apolipoprotein E3/genetics ; Apolipoprotein E4/genetics ; Apolipoproteins E/genetics ; COVID-19/genetics ; COVID-19/mortality ; COVID-19/virology ; Human Genetics ; Mice, Transgenic/genetics ; Mice, Transgenic/virology ; Prospective Studies ; SARS-CoV-2/pathogenicity ; Disease Models, Animal
    Chemical Substances Apolipoprotein E2 ; Apolipoprotein E3 ; Apolipoprotein E4 ; Apolipoproteins E
    Language English
    Publishing date 2022-09-21
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-022-05344-2
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  2. Article ; Online: Pan-sarbecovirus prophylaxis with human anti-ACE2 monoclonal antibodies.

    Zhang, Fengwen / Jenkins, Jesse / de Carvalho, Renan V H / Nakandakari-Higa, Sandra / Chen, Teresia / Abernathy, Morgan E / Baharani, Viren A / Nyakatura, Elisabeth K / Andrew, David / Lebedeva, Irina V / Lorenz, Ivo C / Hoffmann, H-Heinrich / Rice, Charles M / Victora, Gabriel D / Barnes, Christopher O / Hatziioannou, Theodora / Bieniasz, Paul D

    Nature microbiology

    2023  Volume 8, Issue 6, Page(s) 1051–1063

    Abstract: Human monoclonal antibodies (mAbs) that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been isolated from convalescent individuals and developed into therapeutics for SARS-CoV-2 infection. However, therapeutic ... ...

    Abstract Human monoclonal antibodies (mAbs) that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been isolated from convalescent individuals and developed into therapeutics for SARS-CoV-2 infection. However, therapeutic mAbs for SARS-CoV-2 have been rendered obsolete by the emergence of mAb-resistant virus variants. Here we report the generation of a set of six human mAbs that bind the human angiotensin-converting enzyme-2 (hACE2) receptor, rather than the SARS-CoV-2 spike protein. We show that these antibodies block infection by all hACE2 binding sarbecoviruses tested, including SARS-CoV-2 ancestral, Delta and Omicron variants at concentrations of ~7-100 ng ml
    MeSH term(s) Humans ; Animals ; Mice ; Severe acute respiratory syndrome-related coronavirus ; SARS-CoV-2 ; COVID-19/prevention & control ; Antibodies, Monoclonal/pharmacology
    Chemical Substances spike protein, SARS-CoV-2 ; Antibodies, Monoclonal
    Language English
    Publishing date 2023-05-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ISSN 2058-5276
    ISSN (online) 2058-5276
    DOI 10.1038/s41564-023-01389-9
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  3. Article ; Online: E3 ubiquitin ligase Mindbomb 1 facilitates nuclear delivery of adenovirus genomes.

    Sarbanes, Stephanie L / Blomen, Vincent A / Lam, Eric / Heissel, Søren / Luna, Joseph M / Brummelkamp, Thijn R / Falck-Pedersen, Erik / Hoffmann, H-Heinrich / Rice, Charles M

    Proceedings of the National Academy of Sciences of the United States of America

    2020  Volume 118, Issue 1

    Abstract: The journey from plasma membrane to nuclear pore is a critical step in the lifecycle of DNA viruses, many of which must successfully deposit their genomes into the nucleus for replication. Viral capsids navigate this vast distance through the coordinated ...

    Abstract The journey from plasma membrane to nuclear pore is a critical step in the lifecycle of DNA viruses, many of which must successfully deposit their genomes into the nucleus for replication. Viral capsids navigate this vast distance through the coordinated hijacking of a number of cellular host factors, many of which remain unknown. We performed a gene-trap screen in haploid cells to identify host factors for adenovirus (AdV), a DNA virus that can cause severe respiratory illness in immune-compromised individuals. This work identified Mindbomb 1 (MIB1), an E3 ubiquitin ligase involved in neurodevelopment, as critical for AdV infectivity. In the absence of MIB1, we observed that viral capsids successfully traffic to the proximity of the nucleus but ultimately fail to deposit their genomes within. The capacity of MIB1 to promote AdV infection was dependent on its ubiquitination activity, suggesting that MIB1 may mediate proteasomal degradation of one or more negative regulators of AdV infection. Employing complementary proteomic approaches to characterize proteins proximal to MIB1 upon AdV infection and differentially ubiquitinated in the presence or absence of MIB1, we observed an intersection between MIB1 and ribonucleoproteins (RNPs) largely unexplored in mammalian cells. This work uncovers yet another way that viruses utilize host cell machinery for their own replication, highlighting a potential target for therapeutic interventions that counter AdV infection.
    MeSH term(s) A549 Cells ; Adenoviridae/genetics ; Adenoviridae Infections/genetics ; Adenoviridae Infections/metabolism ; HEK293 Cells ; HeLa Cells ; Host-Pathogen Interactions ; Humans ; Nuclear Pore/metabolism ; Protein Binding ; Proteomics ; Ribonucleoproteins/metabolism ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitin-Protein Ligases/physiology ; Ubiquitination ; Virion/metabolism ; Virus Replication/physiology
    Chemical Substances Ribonucleoproteins ; Ubiquitin ; MIB1 ligase, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2020-12-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2015794118
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    Zs.A 1148: Show issues Location:
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  4. Article ; Online: Diverse Viruses Require the Calcium Transporter SPCA1 for Maturation and Spread.

    Hoffmann, H-Heinrich / Schneider, William M / Blomen, Vincent A / Scull, Margaret A / Hovnanian, Alain / Brummelkamp, Thijn R / Rice, Charles M

    Cell host & microbe

    2017  Volume 22, Issue 4, Page(s) 460–470.e5

    Abstract: Respiratory and arthropod-borne viral infections are a global threat due to the lack of effective antivirals and vaccines. A potential strategy is to target host proteins required for viruses but non-essential for the host. To identify such proteins, we ... ...

    Abstract Respiratory and arthropod-borne viral infections are a global threat due to the lack of effective antivirals and vaccines. A potential strategy is to target host proteins required for viruses but non-essential for the host. To identify such proteins, we performed a genome-wide knockout screen in human haploid cells and identified the calcium pump SPCA1. SPCA1 is required by viruses from the Paramyxoviridae, Flaviviridae, and Togaviridae families, including measles, dengue, West Nile, Zika, and chikungunya viruses. Calcium transport activity is required for SPCA1 to promote virus spread. SPCA1 regulates proteases within the trans-Golgi network that require calcium for their activity and are critical for virus glycoprotein maturation. Consistent with these findings, viral glycoproteins fail to mature in SPCA1-deficient cells preventing viral spread, which is evident even in cells with partial loss of SPCA1. Thus, SPCA1 is an attractive antiviral host target for a broad spectrum of established and emerging viral infections.
    MeSH term(s) A549 Cells ; Animals ; Calcium/metabolism ; Calcium-Transporting ATPases/genetics ; Calcium-Transporting ATPases/metabolism ; Chlorocebus aethiops ; Female ; Flaviviridae/physiology ; Gene Knockout Techniques ; Genome-Wide Association Study ; Haploidy ; HeLa Cells ; Host-Pathogen Interactions ; Humans ; Male ; Paramyxoviridae/physiology ; Togaviridae/physiology ; Vero Cells ; Viral Proteins/genetics ; Viral Proteins/metabolism ; trans-Golgi Network/enzymology
    Chemical Substances Viral Proteins ; ATP2C1 protein, human (EC 7.2.2.10) ; Calcium-Transporting ATPases (EC 7.2.2.10) ; Calcium (SY7Q814VUP)
    Keywords covid19
    Language English
    Publishing date 2017-10-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2278004-X
    ISSN 1934-6069 ; 1931-3128
    ISSN (online) 1934-6069
    ISSN 1931-3128
    DOI 10.1016/j.chom.2017.09.002
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  5. Article ; Online: Human anti-ACE2 monoclonal antibodies as pan-sarbecovirus prophylactic agents

    Zhang, Fengwen / Jenkins, Jesse / de Carvalho, Renan V.H. / Nakandakari-Higa, Sandra / Chen, Teresia / Abernathy, Morgan E / Nyakatura, Elisabeth / Andrew, David / Lebedeva, Irina V. / Lorenz, Ivo C / Hoffmann, H.-Heinrich / Rice, Charles M. / Victora, Gabriel D. / Barnes, Christopher O. / Hatziioannou, Theodora / Bieniasz, Paul D

    bioRxiv

    Abstract: Human monoclonal antibodies from convalescent individuals that target the SARS-CoV-2 spike protein have been deployed as therapeutics against SARS-CoV-2. However, nearly all of these antibodies have been rendered obsolete by SARS-CoV-2 variants that ... ...

    Abstract Human monoclonal antibodies from convalescent individuals that target the SARS-CoV-2 spike protein have been deployed as therapeutics against SARS-CoV-2. However, nearly all of these antibodies have been rendered obsolete by SARS-CoV-2 variants that evolved to resist similar, naturally occurring antibodies. Here, we describe the development of human monoclonal antibodies that bind the ACE2 receptor rather than the viral spike protein. These antibodies block infection by all ACE2 binding sarbecoviruses, including emergent SARS-CoV-2 variants. Structural and biochemical analyses revealed that the antibodies target an ACE2 epitope that engages SARS-CoV-2 spike. Importantly, the antibodies do not inhibit ACE2 enzymatic activity, nor do they induce ACE depletion from cell surfaces. The antibodies exhibit favorable pharmacology and protect human ACE2 knock-in mice against SARS-CoV-2 infection. Such antibodies should be useful prophylactic and treatment agents against any current and future SARS-CoV-2 variants, as well as ACE2-binding sarbecoviruses that might emerge as future pandemic threats
    Keywords covid19
    Language English
    Publishing date 2022-08-24
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2022.08.24.505169
    Database COVID19

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  6. 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
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  7. Article: TMEM41B is a pan-flavivirus host factor.

    Hoffmann, H-Heinrich / Schneider, William M / Rozen-Gagnon, Kathryn / Miles, Linde A / Schuster, Felix / Razooky, Brandon / Jacobson, Eliana / Wu, Xianfang / Yi, Soon / Rudin, Charles M / MacDonald, Margaret R / McMullan, Laura K / Poirier, John T / Rice, Charles M

    bioRxiv : the preprint server for biology

    2020  

    Abstract: Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection we performed full-genome loss of ...

    Abstract Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the
    Highlights: TMEM41B and VMP1 are required for both autophagy and flavivirus infection, however, autophagy is not required for flavivirus infection.TMEM41B associates with viral proteins and likely facilitates membrane remodeling to establish viral RNA replication complexes.TMEM41B single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection.TMEM41B-deficient cells display an exaggerated innate immune response upon high multiplicity flavivirus infection.
    Keywords covid19
    Language English
    Publishing date 2020-10-11
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2020.10.09.334128
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  8. Article ; Online: TMEM41B Is a Pan-flavivirus Host Factor.

    Hoffmann, H-Heinrich / Schneider, William M / Rozen-Gagnon, Kathryn / Miles, Linde A / Schuster, Felix / Razooky, Brandon / Jacobson, Eliana / Wu, Xianfang / Yi, Soon / Rudin, Charles M / MacDonald, Margaret R / McMullan, Laura K / Poirier, John T / Rice, Charles M

    Cell

    2020  Volume 184, Issue 1, Page(s) 133–148.e20

    Abstract: Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection, we performed full-genome loss ... ...

    Abstract Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection, we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results, we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms present at nearly 20% in East Asian populations reduce flavivirus infection. Based on our mechanistic studies, we propose that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication.
    MeSH term(s) Animals ; Asian People/genetics ; Autophagy ; COVID-19/genetics ; COVID-19/metabolism ; COVID-19/virology ; CRISPR-Cas Systems ; Cell Line ; Flavivirus/physiology ; Flavivirus Infections/genetics ; Flavivirus Infections/immunology ; Flavivirus Infections/metabolism ; Flavivirus Infections/virology ; Gene Knockout Techniques ; Genome-Wide Association Study ; Host-Pathogen Interactions ; Humans ; Immunity, Innate ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Polymorphism, Single Nucleotide ; SARS-CoV-2/physiology ; Virus Replication ; Yellow fever virus/physiology ; Zika Virus/physiology
    Chemical Substances Membrane Proteins ; TMEM41B protein, human ; VMP1 protein, human
    Language English
    Publishing date 2020-12-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2020.12.005
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    Zs.A 1167: Show issues Location:
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  9. Article ; Online: A CRISPR Activation Screen Identifies an Atypical Rho GTPase That Enhances Zika Viral Entry.

    Luu, Anh Phuong / Yao, Zhenlan / Ramachandran, Sangeetha / Azzopardi, Stephanie A / Miles, Linde A / Schneider, William M / Hoffmann, H-Heinrich / Bozzacco, Leonia / Garcia, Gustavo / Gong, Danyang / Damoiseaux, Robert / Tang, Hengli / Morizono, Kouki / Rudin, Charles M / Sun, Ren / Arumugaswami, Vaithilingaraja / Poirier, John T / MacDonald, Margaret R / Rice, Charles M /
    Li, Melody M H

    Viruses

    2021  Volume 13, Issue 11

    Abstract: Zika virus (ZIKV) is a re-emerging flavivirus that has caused large-scale epidemics. Infection during pregnancy can lead to neurologic developmental abnormalities in children. There is no approved vaccine or therapy for ZIKV. To uncover cellular pathways ...

    Abstract Zika virus (ZIKV) is a re-emerging flavivirus that has caused large-scale epidemics. Infection during pregnancy can lead to neurologic developmental abnormalities in children. There is no approved vaccine or therapy for ZIKV. To uncover cellular pathways required for ZIKV that can be therapeutically targeted, we transcriptionally upregulated all known human coding genes with an engineered CRISPR-Cas9 activation complex in human fibroblasts deficient in interferon (IFN) signaling. We identified Ras homolog family member V (
    MeSH term(s) A549 Cells ; CRISPR-Cas Systems ; GTP-Binding Proteins/genetics ; GTP-Binding Proteins/metabolism ; Humans ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Transcriptional Coactivator with PDZ-Binding Motif Proteins/genetics ; Transcriptional Coactivator with PDZ-Binding Motif Proteins/metabolism ; Virus Internalization ; Virus Replication ; Zika Virus/genetics ; Zika Virus/physiology ; Zika Virus Infection/enzymology ; Zika Virus Infection/genetics ; Zika Virus Infection/virology ; p21-Activated Kinases/genetics ; p21-Activated Kinases/metabolism ; rhoB GTP-Binding Protein/genetics ; rhoB GTP-Binding Protein/metabolism
    Chemical Substances Neoplasm Proteins ; RHOB protein, human ; RHOV protein, human ; Transcriptional Coactivator with PDZ-Binding Motif Proteins ; WWTR1 protein, human ; PAK1 protein, human (EC 2.7.11.1) ; p21-Activated Kinases (EC 2.7.11.1) ; GTP-Binding Proteins (EC 3.6.1.-) ; rhoB GTP-Binding Protein (EC 3.6.5.2)
    Language English
    Publishing date 2021-10-20
    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/v13112113
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  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
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