{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T04:40:21Z","timestamp":1793248821081,"version":"4.5.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T00:00:00Z","timestamp":1684454400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T00:00:00Z","timestamp":1684454400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIGMS T 34 GM070387"],"award-info":[{"award-number":["NIGMS T 34 GM070387"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Commun Signal"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Zika virus (ZIKV), an arbovirus of global concern, has been associated with neurological complications including microcephaly in newborns and Guillain\u2013Barr\u00e9 syndrome in adults. Like other flaviviruses, ZIKV depends on cholesterol to facilitate its replication; thus, cholesterol has been proposed as a therapeutic target to treat the infection using FDA-approved statins. Cholesterol is stored in intracellular lipid droplets (LD) in the form of cholesterol esters and can be regulated by autophagy. We hypothesize that the virus hijacks autophagy machinery as an early step to increase the formation of LD and viral replication, and that interference with this pathway will limit reproduction of virus.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We pretreated MDCK cells with atorvastatin or other inhibitors of autophagy prior to infection with ZIKV. We measured viral expression by qPCR for NS1 RNA and immunofluorescence for Zika E protein.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Autophagy increases in virus-infected cells as early as 6\u00a0h post infection (hpi). In the presence of atorvastatin, LD are decreased, and cholesterol is reduced, targeting key steps in viral replication, resulting in suppression of replication of ZIKV is suppressed. Other both early- and late-acting autophagy inhibitors decrease both the number of LD and viral replication. Bafilomycin renders cholesterol is inaccessible to ZIKV. We also confirm previous reports of a bystander effect, in which neighboring uninfected cells have higher LD counts compared to infected cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We conclude that atorvastatin and inhibitors of autophagy lead to lower availability of LD, decreasing viral replication. We conclude that bafilomycin A1 inhibits viral expression by blocking cholesterol esterification to form LD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s12964-022-01026-8","type":"journal-article","created":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T09:02:23Z","timestamp":1684486943000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Zika virus triggers autophagy to exploit host lipid metabolism and drive viral replication"],"prefix":"10.1186","volume":"21","author":[{"given":"Gloria","family":"Stoyanova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidra","family":"Jabeen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joselyn","family":"Landazuri Vinueza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sounak","family":"Ghosh Roy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Lockshin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Zakeri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,19]]},"reference":[{"issue":"4","key":"1026_CR1","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1016\/j.ncl.2016.06.008","volume":"34","author":"DS Younger","year":"2016","unstructured":"Younger DS. Epidemiology of Zika virus. Neurol Clin. 2016;34(4):1049\u201356.","journal-title":"Neurol Clin"},{"issue":"5","key":"1026_CR2","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/0035-9203(52)90042-4","volume":"46","author":"GWA Dick","year":"1952","unstructured":"Dick GWA, Kitchen SF, Haddow AJ. Zika virus (I). Isolations and serological specificity. Trans R Soc Trop Med Hyg. 1952;46(5):509\u201320.","journal-title":"Trans R Soc Trop Med Hyg"},{"issue":"10","key":"1026_CR3","doi-asserted-by":"publisher","first-page":"S860","DOI":"10.1093\/infdis\/jix451","volume":"216","author":"DJ Gubler","year":"2017","unstructured":"Gubler DJ, Vasilakis N, Musso D. History and emergence of Zika virus. J Infect Dis. 2017;216(10):S860\u20137.","journal-title":"J Infect Dis"},{"issue":"6","key":"1026_CR4","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/S1473-3099(16)00095-5","volume":"16","author":"G Calvet","year":"2016","unstructured":"Calvet G, Aguiar RS, Melo ASO, Sampaio SA, de Filippis I, Fabri A, et al. Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study. Lancet Infect Dis. 2016;16(6):653\u201360.","journal-title":"Lancet Infect Dis"},{"issue":"10","key":"1026_CR5","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1056\/NEJMoa1600651","volume":"374","author":"J Mlakar","year":"2016","unstructured":"Mlakar J, Korva M, Tul N, Popovi\u0107 M, Polj\u0161ak-Prijatelj M, Mraz J, et al. Zika virus associated with microcephaly. N Engl J Med. 2016;374(10):951\u20138.","journal-title":"N Engl J Med"},{"issue":"4","key":"1026_CR6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004636","volume":"10","author":"P Brasil","year":"2016","unstructured":"Brasil P, Calvet GA, Siqueira AM, Wakimoto M, de Sequeira PC, Nobre A, et al. Zika virus outbreak in Rio de Janeiro, Brazil: clinical characterization, epidemiological and virological aspects. PLoS Negl Trop Dis. 2016;10(4): e0004636.","journal-title":"PLoS Negl Trop Dis"},{"issue":"5","key":"1026_CR7","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.4269\/ajtmh.16-0306","volume":"95","author":"MS do Ros\u00e1rio","year":"2016","unstructured":"do Ros\u00e1rio MS, de Jesus PAP, Vasilakis N, Farias DS, Novaes MAC, Rodrigues SG, et al. Guillain\u2013Barr\u00e9 syndrome after Zika virus infection in Brazil. Am J Trop Med Hyg. 2016;95(5):1157\u201360.","journal-title":"Am J Trop Med Hyg"},{"issue":"9","key":"1026_CR8","doi-asserted-by":"publisher","first-page":"2113","DOI":"10.1016\/j.celrep.2017.02.014","volume":"18","author":"M Cortese","year":"2017","unstructured":"Cortese M, Goellner S, Acosta EG, Neufeldt CJ, Oleksiuk O, Lampe M, et al. Ultrastructural characterization of Zika virus replication factories. Cell Rep. 2017;18(9):2113\u201323.","journal-title":"Cell Rep"},{"issue":"11","key":"1026_CR9","doi-asserted-by":"publisher","first-page":"1905","DOI":"10.15252\/embr.201643426","volume":"18","author":"J Jacquemyn","year":"2017","unstructured":"Jacquemyn J, Cascalho A, Goodchild RE. The ins and outs of endoplasmic reticulum-controlled lipid biosynthesis. EMBO Rep. 2017;18(11):1905\u201321.","journal-title":"EMBO Rep"},{"issue":"1","key":"1026_CR10","doi-asserted-by":"publisher","first-page":"3652","DOI":"10.1038\/s41467-020-17433-9","volume":"11","author":"HC Leier","year":"2020","unstructured":"Leier HC, Weinstein JB, Kyle JE, Lee JY, Bramer LM, Stratton KG, et al. A global lipid map defines a network essential for Zika virus replication. Nat Commun. 2020;11(1):3652.","journal-title":"Nat Commun"},{"key":"1026_CR11","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2018.00388","author":"JF Osuna-Ramos","year":"2018","unstructured":"Osuna-Ramos JF, Reyes-Ruiz JM, del \u00c1ngel RM. The role of host cholesterol during flavivirus infection. Front Cell Infect Microbiol. 2018. https:\/\/doi.org\/10.3389\/fcimb.2018.00388.","journal-title":"Front Cell Infect Microbiol"},{"key":"1026_CR12","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.00286","author":"Z Zhang","year":"2019","unstructured":"Zhang Z, He G, Filipowicz NA, Randall G, Belov GA, Kopek BG, et al. Host lipids in positive-strand RNA virus genome replication. Front Microbiol. 2019. https:\/\/doi.org\/10.3389\/fmicb.2019.00286.","journal-title":"Front Microbiol"},{"issue":"8","key":"1026_CR13","first-page":"686","volume":"43","author":"DW Shin","year":"2020","unstructured":"Shin DW. Lipophagy: molecular mechanisms and implications in metabolic disorders. Mol Cells. 2020;43(8):686\u201393.","journal-title":"Mol Cells"},{"issue":"479\u2013480","key":"1026_CR14","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.virol.2015.03.042","volume":"1","author":"WT Jackson","year":"2015","unstructured":"Jackson WT. Viruses and the autophagy pathway. Virology. 2015;1(479\u2013480):450\u20136.","journal-title":"Virology"},{"issue":"6","key":"1026_CR15","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1038\/s41579-018-0003-6","volume":"16","author":"Y Choi","year":"2018","unstructured":"Choi Y, Bowman JW, Jung JU. Autophagy during viral infection\u2014a double-edged sword. Nat Rev Microbiol. 2018;16(6):341\u201354.","journal-title":"Nat Rev Microbiol"},{"issue":"3","key":"1026_CR16","doi-asserted-by":"publisher","first-page":"321","DOI":"10.4161\/auto.5.3.7406","volume":"5","author":"Z Zhou","year":"2009","unstructured":"Zhou Z, Jiang X, Liu D, Fan Z, Hu X, Yan J, et al. Autophagy is involved in influenza A virus replication. Autophagy. 2009;5(3):321\u20138.","journal-title":"Autophagy"},{"issue":"2","key":"1026_CR17","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.virol.2008.02.016","volume":"374","author":"YR Lee","year":"2008","unstructured":"Lee YR, Lei HY, Liu MT, Wang JR, Chen SH, Jiang-Shieh YF, et al. Autophagic machinery activated by dengue virus enhances virus replication. Virology. 2008;374(2):240\u20138.","journal-title":"Virology"},{"issue":"8","key":"1026_CR18","doi-asserted-by":"publisher","first-page":"224","DOI":"10.3390\/v9080224","volume":"9","author":"ST Chan","year":"2017","unstructured":"Chan ST, Ou JJ. Hepatitis C virus-induced autophagy and host innate immune response. Viruses. 2017;9(8):224.","journal-title":"Viruses"},{"issue":"254","key":"1026_CR19","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.virusres.2017.09.006","volume":"2","author":"AI Chiramel","year":"2018","unstructured":"Chiramel AI, Best SM. Role of autophagy in Zika virus infection and pathogenesis. Virus Res. 2018;2(254):34\u201340.","journal-title":"Virus Res"},{"key":"1026_CR20","unstructured":"Ghosh Roy S. Mechanisms adopted by Dengue-2 viruses to induce autophagy in mammalian cells. Diss Theses Capstone Proj [Internet]. 2018. Available from: https:\/\/academicworks.cuny.edu\/gc_etds\/2919."},{"issue":"1","key":"1026_CR21","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/sj.cdd.4401717","volume":"13","author":"L Lin","year":"2006","unstructured":"Lin L, Ye Y, Zakeri Z. p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death. Cell Death Differ. 2006;13(1):141\u201350.","journal-title":"Cell Death Differ"},{"issue":"8","key":"1026_CR22","first-page":"9516","volume":"33","author":"D Episcopio","year":"2019","unstructured":"Episcopio D, Aminov S, Benjamin S, Germain G, Datan E, Landazuri J, et al. Atorvastatin restricts the ability of influenza virus to generate lipid droplets and severely suppresses the replication of the virus. FASEB J Off Publ Fed Am Soc Exp Biol. 2019;33(8):9516\u201325.","journal-title":"FASEB J Off Publ Fed Am Soc Exp Biol"},{"issue":"1","key":"1026_CR23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41420-018-0065-2","volume":"4","author":"Q Yan","year":"2018","unstructured":"Yan Q, Song Y, Zhang L, Chen Z, Yang C, Liu S, et al. Autophagy activation contributes to lipid accumulation in tubular epithelial cells during kidney fibrosis. Cell Death Discov. 2018;4(1):1\u201314.","journal-title":"Cell Death Discov"},{"issue":"36","key":"1026_CR24","doi-asserted-by":"publisher","first-page":"27345","DOI":"10.1016\/S0021-9258(19)74255-0","volume":"268","author":"T Furuchi","year":"1993","unstructured":"Furuchi T, Aikawa K, Arai H, Inoue K. Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, blocks lysosomal cholesterol trafficking in macrophages. J Biol Chem. 1993;268(36):27345\u20138.","journal-title":"J Biol Chem"},{"issue":"20","key":"1026_CR25","doi-asserted-by":"publisher","first-page":"10438","DOI":"10.1128\/JVI.00986-10","volume":"84","author":"LK Gillespie","year":"2010","unstructured":"Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J Virol. 2010;84(20):10438\u201347.","journal-title":"J Virol"},{"issue":"64","key":"1026_CR26","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.plipres.2016.09.005","volume":"1","author":"MA Mart\u00edn-Acebes","year":"2016","unstructured":"Mart\u00edn-Acebes MA, V\u00e1zquez-Calvo \u00c1, Saiz JC. Lipids and flaviviruses, present and future perspectives for the control of dengue, Zika, and West Nile viruses. Prog Lipid Res. 2016;1(64):123\u201337.","journal-title":"Prog Lipid Res"},{"issue":"3","key":"1026_CR27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002584","volume":"8","author":"R Perera","year":"2012","unstructured":"Perera R, Riley C, Isaac G, Hopf-Jannasch AS, Moore RJ, Weitz KW, et al. Dengue virus infection perturbs lipid homeostasis in infected mosquito cells. PLOS Pathog. 2012;8(3): e1002584.","journal-title":"PLOS Pathog"},{"issue":"1","key":"1026_CR28","doi-asserted-by":"publisher","first-page":"2967","DOI":"10.1038\/s41467-020-16754-z","volume":"11","author":"Q Chen","year":"2020","unstructured":"Chen Q, Gouilly J, Ferrat YJ, Espino A, Glaziou Q, Cartron G, et al. Metabolic reprogramming by Zika virus provokes inflammation in human placenta. Nat Commun. 2020;11(1):2967.","journal-title":"Nat Commun"},{"issue":"4","key":"1026_CR29","doi-asserted-by":"publisher","first-page":"2432","DOI":"10.1128\/JVI.79.4.2432-2439.2005","volume":"79","author":"DR Palmer","year":"2005","unstructured":"Palmer DR, Sun P, Celluzzi C, Bisbing J, Pang S, Sun W, et al. Differential effects of dengue virus on infected and bystander dendritic cells. J Virol. 2005;79(4):2432\u20139.","journal-title":"J Virol"},{"issue":"41","key":"1026_CR30","doi-asserted-by":"publisher","first-page":"14641","DOI":"10.1073\/pnas.0505473102","volume":"102","author":"H Zhou","year":"2005","unstructured":"Zhou H, Ivanov VN, Gillespie J, Geard CR, Amundson SA, Brenner DJ, et al. Mechanism of radiation-induced bystander effect: role of the cyclooxygenase-2 signaling pathway. Proc Natl Acad Sci. 2005;102(41):14641\u20136.","journal-title":"Proc Natl Acad Sci"},{"issue":"1","key":"1026_CR31","doi-asserted-by":"publisher","first-page":"37433","DOI":"10.1038\/srep37433","volume":"6","author":"HM Kofahi","year":"2016","unstructured":"Kofahi HM, Taylor NGA, Hirasawa K, Grant MD, Russell RS. Hepatitis C virus infection of cultured human hepatoma cells causes apoptosis and pyroptosis in both infected and bystander cells. Sci Rep. 2016;6(1):37433.","journal-title":"Sci Rep"},{"issue":"2","key":"1026_CR32","doi-asserted-by":"publisher","first-page":"97","DOI":"10.3390\/ph12020097","volume":"12","author":"MA Mart\u00edn-Acebes","year":"2019","unstructured":"Mart\u00edn-Acebes MA, Jim\u00e9nez de Oya N, Saiz JC. Lipid metabolism as a source of druggable targets for antiviral discovery against Zika and other flaviviruses. Pharmaceuticals. 2019;12(2):97.","journal-title":"Pharmaceuticals"},{"issue":"1","key":"1026_CR33","doi-asserted-by":"publisher","first-page":"11461","DOI":"10.1038\/s41598-019-47956-1","volume":"9","author":"E Espa\u00f1o","year":"2019","unstructured":"Espa\u00f1o E, Nam JH, Song EJ, Song D, Lee CK, Kim JK. Lipophilic statins inhibit Zika virus production in Vero cells. Sci Rep. 2019;9(1):11461.","journal-title":"Sci Rep"},{"issue":"5","key":"1026_CR34","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/j.chom.2010.10.006","volume":"8","author":"NS Heaton","year":"2010","unstructured":"Heaton NS, Randall G. Dengue virus-induced autophagy regulates lipid metabolism. Cell Host Microbe. 2010;8(5):422\u201332.","journal-title":"Cell Host Microbe"},{"issue":"6","key":"1026_CR35","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1016\/j.chom.2018.05.005","volume":"23","author":"J Zhang","year":"2018","unstructured":"Zhang J, Lan Y, Li MY, Lamers MM, Fusade-Boyer M, Klemm E, et al. Flaviviruses exploit the lipid droplet protein AUP1 to trigger lipophagy and drive virus production. Cell Host Microbe. 2018;23(6):819-831.e5.","journal-title":"Cell Host Microbe"}],"container-title":["Cell Communication and Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12964-022-01026-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12964-022-01026-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12964-022-01026-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T09:10:31Z","timestamp":1684487431000},"score":1,"resource":{"primary":{"URL":"https:\/\/biosignaling.biomedcentral.com\/articles\/10.1186\/s12964-022-01026-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,19]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["1026"],"URL":"https:\/\/doi.org\/10.1186\/s12964-022-01026-8","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-2196572\/v1","asserted-by":"object"}]},"ISSN":["1478-811X"],"issn-type":[{"value":"1478-811X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,19]]},"assertion":[{"value":"23 October 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 December 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 May 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"114"}}