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• W3113134471 abstract "Complementary genome-wide CRISPR-Cas9 screens performed by multiple groups reveal new insights into SARS-CoV-2 biology including aspects of viral entry, translation, replication, egress, and the genes regulating these processes. Comparisons with other coronaviruses enhances our understanding of the cellular life cycle of this medically important family of emerging viruses. Complementary genome-wide CRISPR-Cas9 screens performed by multiple groups reveal new insights into SARS-CoV-2 biology including aspects of viral entry, translation, replication, egress, and the genes regulating these processes. Comparisons with other coronaviruses enhances our understanding of the cellular life cycle of this medically important family of emerging viruses. Over the past 5 years, CRISPR-based screening has fueled a wave of remarkable discoveries in cell biology, and virus-host interactions have been no exception (Puschnik et al., 2017Puschnik A.S. Majzoub K. Ooi Y.S. Carette J.E. A CRISPR toolbox to study virus-host interactions.Nat. Rev. Microbiol. 2017; 15: 351-364Crossref PubMed Scopus (109) Google Scholar). Many groups have generated cell lines transduced with libraries of small guide (sg)RNAs that cause insertions or deletions in a single gene per cell, disabling expression or function of the respective protein. Survival screens with cytolytic viruses conducted over a few weeks’ period results in the outgrowth of cells resistant to infection and death. Although this approach cannot identify proviral factors that also are essential for cell viability, it is nonetheless a proven and robust approach for identifying many host factors required for viral infection (e.g., receptors), which is accomplished by sequencing of the gene-specific sgRNA in the surviving cells. In this issue of Cell, three new articles (Hoffmann et al., 2020cHoffmann H.-H. Schneider W.M. Rozen-Gagnon K. Miles L.A. Schuster F. Razooky B. Jacobson E. Wu X. Yi S. Rudin C.M. et al.TMEM41B is a pan-flavivirus host factor.Cell. 2020; 184 (this issue): 133-148Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar; Schneider et al., 2020Schneider W.M. Luna J.M. Hoffmann H.-H. Sánchez-Rivera F.J. Leal A.A. Ashbrook A.W. Le Pen J. Ricardo-Lax I. Michailidis E. Peace A. et al.Genome-Scale Identification of SARS-CoV-2 and Pan-coronavirus Host Factor Networks.Cell. 2020; 184 (this issue): 120-132Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar; Wang et al., 2020Wang R. Simoneau C.R. Kulsuptrakul J. Bouhaddou M. Travisano K.A. Hayashi J.M. Carlson-Stevermer J. Zengel J.R. Richards C.M. Fozouni P. et al.Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses.Cell. 2020; 184 (this issue): 106-119Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar) add to a growing list of host proteins required for SARS-CoV-2 infection that have been identified using CRISPR-based survival screens (Daniloski et al., 2020Daniloski Z. Jordan T.X. Wessels H.-H. Hoagland D.A. Kasela S. Legut M. Maniatis S. Mimitou E.P. Lu L. Geller E. et al.Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells.Cell. 2020; 184 (this issue): 92-105Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar; Wei et al., 2020Wei J. Alfajaro M.M. DeWeirdt P.C. Hanna R.E. Lu-Culligan W.J. Cai W.L. Strine M.S. Zhang S.-M. Graziano V.R. Schmitz C.O. et al.Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection.Cell. 2020; 184 (this issue): 76-91Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar). Collectively, these five groups used several different sgRNA libraries (Brunello, GeCKO, and GeCKOv2) and multiple human or monkey lines derived from lung, liver, kidney, and myeloid cells (aided in some instances by exogenous expression of human ACE2, the SARS-CoV-2 receptor) to generate a wealth of information on SARS-CoV-2 biology that will serve as a foundation for the field to study for years to come. Several of the screens cross-validate one another’s findings by identifying the same gene or sets of genes that encode for proteins forming discrete functional complexes or pathways within the cell. Although the precise role that many of these proteins have in the viral life cycle is undetermined, their presumptive subcellular location provides insight into the biology of SARS-CoV-2 (Figure 1). Beginning with SARS-CoV-2 attachment to the cell surface, several screens identified genes regulating steps in the biosynthesis of glycosaminoglycans (GAGs) in addition to the proteinaceous receptor, ACE2. GAGs are negatively charged polysaccharides that decorate the cell surface and likely enhance infectivity by attracting and concentrating viruses, which often contain exposed patches of positive charge, onto the cell surface. Notably, many of the additional SARS-CoV-2 attachment factors recently reported (e.g., neuropilin-1 and HDL-scavenger receptor B type 1) were not identified in these screens. Endosomal cathepsins (e.g., cathepsin L), which function to cleave and activate the SARS-CoV-2 spike protein and facilitate fusion of the viral and endosome membranes, were found in multiple screens along with the endosomal GTPase Rab7a. Notably, these genes were not identified as proviral factors in screens that utilized cells ectopically expressing TMPRSS2 (Wang et al., 2020Wang R. Simoneau C.R. Kulsuptrakul J. Bouhaddou M. Travisano K.A. Hayashi J.M. Carlson-Stevermer J. Zengel J.R. Richards C.M. Fozouni P. et al.Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses.Cell. 2020; 184 (this issue): 106-119Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar), a serine protease on the plasma membrane that primes spike activation and promotes SARS-CoV-2 entry into cells via direct fusion, bypassing the endocytic entry pathway (Simmons et al., 2013Simmons G. Zmora P. Gierer S. Heurich A. Pöhlmann S. Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research.Antiviral Res. 2013; 100: 605-614Crossref PubMed Scopus (300) Google Scholar). A number of proteins localizing to the endoplasmic reticulum (ER), the ER-Golgi intermediate compartment (ERGIC), and the Golgi apparatus also were identified by the screens as critical for virus-induced infection and cell death, reflecting the roles these compartments have in the translation of SARS-CoV-2 structural proteins and virion assembly. Among the ER host factors identified as important for SARS-CoV-2 infection is the relatively obscure protein TMEM41B, which Hoffmann and colleagues also defined as an essential host factor for viruses of the Flaviviridae family (Hoffmann et al., 2020cHoffmann H.-H. Schneider W.M. Rozen-Gagnon K. Miles L.A. Schuster F. Razooky B. Jacobson E. Wu X. Yi S. Rudin C.M. et al.TMEM41B is a pan-flavivirus host factor.Cell. 2020; 184 (this issue): 133-148Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). TMEM41B shapes the ER membrane into structures conducive to the formation of viral replication factories. ER-localized proteins involved in cholesterol homeostasis (e.g., SREBP, SCAP, and MBTPS1/2) also feature prominently in several screens, although different groups identified both positive and negative regulators of cholesterol biosynthesis as antiviral. While this discrepancy could be explained by idiosyncrasies of the particular screens or cell types used, it highlights how poorly understood this host process is for the SARS-CoV-2 life cycle. Finally, several additional host factors were identified as important for the egress stage of the viral life cycle. While also relatively poorly understood, recent work identified lysosomal exocytosis as a pathway by which coronaviruses exit infected cells (Ghosh et al., 2020Ghosh S. Dellibovi-Ragheb T.A. Kerviel A. Pak E. Qiu Q. Fisher M. Takvorian P.M. Bleck C. Hsu V.W. Fehr A.R. et al.β-Coronaviruses Use Lysosomes for Egress Instead of the Biosynthetic Secretory Pathway.Cell. 2020; 183: 1520-1535.e14Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar). In light of this, many of the seemingly disconnected “hits” identified across these screens—the exocyst complex, phosphatidylinositol kinases (PIK3C3, PICfyve), and other pathways related to endosomal recycling (Commander complex, Retromer complex, TMEM106B)—may in fact function in virion internalization and/or egress via lysosomal exocytosis and/or other exocytic pathways. The genes identified in these papers demand further study to achieve a comprehensive understanding of the SARS-CoV-2 life cycle. Such investigation may include distinguishing between factors that interact directly with viral proteins (e.g., SCAP, as suggested by Wang et al., 2020Wang R. Simoneau C.R. Kulsuptrakul J. Bouhaddou M. Travisano K.A. Hayashi J.M. Carlson-Stevermer J. Zengel J.R. Richards C.M. Fozouni P. et al.Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses.Cell. 2020; 184 (this issue): 106-119Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar) from those regulating viral protein interactions with other host proteins (e.g., SWI/SNF, as shown by Wei et al., 2020Wei J. Alfajaro M.M. DeWeirdt P.C. Hanna R.E. Lu-Culligan W.J. Cai W.L. Strine M.S. Zhang S.-M. Graziano V.R. Schmitz C.O. et al.Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection.Cell. 2020; 184 (this issue): 76-91Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar). CRISPR-mediated survival screens in model cell lines are a beginning, as it will be critical to establish the relevance of these proteins and pathways to the biology of SARS-CoV-2 in primary human cells and ultimately in humans. For example, emerging data suggest that SARS-CoV-2 circulating in humans has a preference for TMPRSS2-mediated spike activation (Hoffmann et al., 2020aHoffmann M. Kleine-Weber H. Pöhlmann S. A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells.Mol. Cell. 2020; 78: 779-784.e5Abstract Full Text Full Text PDF PubMed Scopus (1070) Google Scholar) and fusion at the cell membrane as the primary mode of entry in human lung epithelium. However, passage of SARS-CoV-2 in cell lines with low levels of TMPRSS2 (e.g., Vero cells) rapidly selects for variants with mutations in the furin cleavage site that enter cells via endocytosis. These two distinct entry pathways are not mutually exclusive and could vary by cell type in vitro and in vivo (Hoffmann et al., 2020bHoffmann M. Kleine-Weber H. Schroeder S. Krüger N. Herrler T. Erichsen S. Schiergens T.S. Herrler G. Wu N.-H. Nitsche A. et al.SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.Cell. 2020; 181: 271-280.e8Abstract Full Text Full Text PDF PubMed Scopus (12190) Google Scholar; Simmons et al., 2013Simmons G. Zmora P. Gierer S. Heurich A. Pöhlmann S. Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research.Antiviral Res. 2013; 100: 605-614Crossref PubMed Scopus (300) Google Scholar). Nevertheless, the identification of endosomal host factors as proviral in screens that utilized cell lines with low levels of TMPRSS2 expression may require cautious interpretation until validated in primary cells. Many of the gene products and complexes identified in the screens represent targets for host-directed anti-COVID-19 therapy. Indeed, several of the studies present data showing antiviral activity of compounds that target “hits” in the screens (Daniloski et al., 2020Daniloski Z. Jordan T.X. Wessels H.-H. Hoagland D.A. Kasela S. Legut M. Maniatis S. Mimitou E.P. Lu L. Geller E. et al.Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells.Cell. 2020; 184 (this issue): 92-105Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar; Wang et al., 2020Wang R. Simoneau C.R. Kulsuptrakul J. Bouhaddou M. Travisano K.A. Hayashi J.M. Carlson-Stevermer J. Zengel J.R. Richards C.M. Fozouni P. et al.Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses.Cell. 2020; 184 (this issue): 106-119Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar). While the genetic screens should prompt further interrogation of existing compounds and drugs that bind these proviral host factors, biochemical screens for small molecules targeting these pathways more specifically might yield novel classes of host-directed antivirals against SARS-CoV-2 infection. Finally, many of the studies reported comparative effects of specific genes on multiple different coronaviruses (and sometimes other viruses) in addition to SARS-CoV-2. Such an approach may identify shared aspects of virus biology that enables the development of broadly acting antivirals, which could help prepare us for the next viral pandemic, when it comes. M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and the Carnival Corporation and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support from Moderna, Vir Biotechnology, and Emergent BioSolutions. Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 InfectionWei et al.CellOctober 20, 2020In BriefTo identify potential therapeutic targets for SARS-CoV-2 and related pathogenic coronaviruses, Wei et al. conduct genome-wide CRISPR screens in Vero-E6 cells using SARS-CoV-2, MERS-CoV, and pseudoviruses presenting SARS-CoV-1 or SARS-CoV-2 spike proteins. They identify pro-viral genes and pathways, including HMGB1 and the SWI/SNF chromatin remodeling complex, that are SARS lineage and pan-coronavirus specific, respectively, and demonstrate that HMGB1 is critical for SARS lineage viral entry because it has a critical role in ACE2 expression. Full-Text PDF Open ArchiveIdentification of Required Host Factors for SARS-CoV-2 Infection in Human CellsDaniloski et al.CellOctober 24, 2020In BriefTo identify potential therapeutic targets for SARS-CoV-2, Daniloski et al. conduct a genome-wide CRISPR screen in human lung epithelial cells. They identify genes and pathways required for SARS-CoV-2 infection, including the vacuolar ATPase proton pump, Retromer, and Commander complexes. Using single-cell transcriptomics, they identify upregulation of cholesterol biosynthesis as a common mechanism underlying viral resistance, in addition to ACE2 sequestration. Full-Text PDF Open ArchiveTMEM41B Is a Pan-flavivirus Host FactorHoffmann et al.CellDecember 8, 2020In BriefHoffmann et al. determine that the transmembrane protein, TMEM41B, is required for infection by members of the Flaviviridae family of viruses. Loss of TMEM41B reduces viral RNA replication and increases innate immune activation in response to flavivirus infection. Thus, TMEM41B is a potential host target for antiviral therapeutics. Full-Text PDF Open ArchiveGenetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold CoronavirusesWang et al.CellDecember 8, 2020In BriefTo identify host factors required for the infection with SARS-CoV-2 and the common cold coronaviruses OC43 and 229E, Wang et al. conduct genome-wide CRISPR knockout screens. In addition to virus-specific entry factors, they uncover shared host pathways, including cholesterol homeostasis and phosphatidylinositol kinases, required for the infection with all three viruses and demonstrate that pharmacological inhibition of these pathways exhibits pan-coronavirus antiviral activity. Full-Text PDF Open ArchiveGenome-Scale Identification of SARS-CoV-2 and Pan-coronavirus Host Factor NetworksSchneider et al.CellDecember 9, 2020In BriefSchneider et al. conducted parallel genome-wide CRISPR knockout screens with SARS-CoV-2 and three seasonal coronaviruses to identify pan-coronavirus and virus-specific host factor requirements. They identified an interconnected network of host factors required by these four viruses and validated TMEM41B as a pan-coronavirus host factor required for a post-entry step in the coronavirus life cycle. Full-Text PDF Open Archive" @default.
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• W3113134471 title "A Crisp(r) New Perspective on SARS-CoV-2 Biology" @default.
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