{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:41:31Z","timestamp":1790700091695,"version":"4.1.0"},"reference-count":104,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T00:00:00Z","timestamp":1724284800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Advanced Customer Cultivation Project of Wuhan National Biosafety Laboratory, Chinese Academy of Sciences","award":["2021ACCP-MS03"],"award-info":[{"award-number":["2021ACCP-MS03"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82341084"],"award-info":[{"award-number":["82341084"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272302"],"award-info":[{"award-number":["82272302"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82241077"],"award-info":[{"award-number":["82241077"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32070153"],"award-info":[{"award-number":["32070153"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine"},{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["Z220018"],"award-info":[{"award-number":["Z220018"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Tsinghua University Dushi Program","award":["20231080039"],"award-info":[{"award-number":["20231080039"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>The Ebola virus (EBOV) has emerged as a significant global health concern, notably during the 2013\u20132016 outbreak in West Africa. Despite the clinical approval of two EBOV antibody drugs, there is an urgent need for more diverse and effective antiviral drugs, along with comprehensive understanding of viral-host interactions. In this study, we harnessed a biologically contained EBOV\u0394VP30-EGFP cell culture model which could recapitulate the entire viral life cycle, to conduct a genome-wide CRISPR\/Cas9 screen. Through this, we identified PIK3C3 (phosphatidylinositide 3-kinase) and SLC39A9 (zinc transporter) as crucial host factors for EBOV infection. Genetic depletion of SLC39A9 and PIK3C3 lead to reduction of EBOV entry, but not impact viral genome replication, suggesting that SLC39A9 and PIK3C3 act as entry factors, facilitating viral entry into host cells. Moreover, PIK3C3 kinase activity is indispensable for the internalization of EBOV virions, presumably through the regulation of endocytic and autophagic membrane traffic, which has been previously recognized as essential for EBOV internalization. Notably, our study demonstrated that PIK3C3 kinase inhibitor could effectively block EBOV infection, underscoring PIK3C3 as a promising drug target. Furthermore, biochemical analysis showed that recombinant SLC39A9 protein could directly bind viral GP protein, which further promotes the interaction of viral GP protein with cellular receptor NPC1. These findings suggests that SLC39A9 plays dual roles in EBOV entry. Initially, it serves as an attachment factor during the early entry phase by engaging with the viral GP protein. Subsequently, SLC39A9 functions an adaptor protein, facilitating the interaction between virions and the NPC1 receptor during the late entry phase, prior to cathepsin cleavage on the viral GP. In summary, this study offers novel insights into virus-host interactions, contributing valuable information for the development of new therapies against EBOV infection.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012444","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T19:42:44Z","timestamp":1724355764000},"page":"e1012444","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Genome-wide CRISPR\/Cas9 screen identifies SLC39A9 and PIK3C3 as crucial entry factors for Ebola virus infection"],"prefix":"10.1371","volume":"20","author":[{"given":"Mingli","family":"Gong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwu","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Shan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6226-869X","authenticated-orcid":true,"given":"Qiang","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,8,22]]},"reference":[{"issue":"10174","key":"ppat.1012444.ref001","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/S0140-6736(18)33132-5","article-title":"Ebola virus disease","volume":"393","author":"D Malvy","year":"2019","journal-title":"The Lancet"},{"issue":"1","key":"ppat.1012444.ref002","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41572-020-0147-3","article-title":"Ebola virus disease","volume":"6","author":"ST Jacob","year":"2020","journal-title":"Nature Reviews Disease Primers"},{"issue":"4","key":"ppat.1012444.ref003","first-page":"953","article-title":"Ebola virus disease: epidemiology, clinical features, management, and prevention","volume":"33","author":"E Nicastri","year":"2019","journal-title":"Infectious Disease Clinics"},{"key":"ppat.1012444.ref004","doi-asserted-by":"crossref","first-page":"102375","DOI":"10.1016\/j.jaut.2019.102375","article-title":"Ebola virus disease: An emerging and re-emerging viral threat","volume":"106","author":"M Rojas","year":"2020","journal-title":"Journal of autoimmunity"},{"key":"ppat.1012444.ref005","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.coph.2021.08.002","article-title":"The 2013\u20132016 Ebola virus disease outbreak in West Africa","volume":"60","author":"EI Ohimain","year":"2021","journal-title":"Current Opinion in Pharmacology"},{"issue":"12","key":"ppat.1012444.ref006","doi-asserted-by":"crossref","first-page":"e1010078","DOI":"10.1371\/journal.ppat.1010078","article-title":"Current state of Ebola virus vaccines: A snapshot","volume":"17","author":"C Woolsey","year":"2021","journal-title":"PLoS pathogens"},{"issue":"6","key":"ppat.1012444.ref007","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1177\/8755122520950692","article-title":"Ervebo (Ebola Zaire vaccine, live\/rVSV\u0394G-ZEBOV-GP): the first licensed vaccine for the prevention of Ebola virus disease","volume":"36","author":"CR Piszczatoski","year":"2020","journal-title":"Journal of Pharmacy Technology"},{"issue":"10","key":"ppat.1012444.ref008","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1016\/S1473-3099(22)00607-7","article-title":"New guidelines for treatment of Ebola virus disease","volume":"22","author":"T. 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