{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:43:52Z","timestamp":1791852232113,"version":"4.3.4"},"reference-count":40,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2020,10,12]],"date-time":"2020-10-12T00:00:00Z","timestamp":1602460800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP19fk010803"],"award-info":[{"award-number":["JP19fk010803"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP20fk0108123"],"award-info":[{"award-number":["JP20fk0108123"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["Kiban-C, #23590803"],"award-info":[{"award-number":["Kiban-C, #23590803"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["Kiban-B, #25300053"],"award-info":[{"award-number":["Kiban-B, #25300053"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Research Program on Emerging and Re-emerging Infectious Diseases, Japan","award":["H26-28"],"award-info":[{"award-number":["H26-28"]}]},{"name":"The Research Program on Emerging and Re-emerging Infectious Diseases, Japan","award":["H29-31"],"award-info":[{"award-number":["H29-31"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Efforts to determine the mosquito genes that affect dengue virus replication have identified a number of candidates that positively or negatively modify amplification in the invertebrate host. We used deep sequencing to compare the differential transcript abundances in Aedes aegypti 14 days post dengue infection to those of uninfected A. aegypti. The gene lethal(2)-essential-for-life [l(2)efl], which encodes a member of the heat shock 20 protein (HSP20) family, was upregulated following dengue virus type 2 (DENV-2) infection in vivo. The transcripts of this gene did not exhibit differential accumulation in mosquitoes exposed to insecticides or pollutants. The induction and overexpression of l(2)efl gene products using poly(I:C) resulted in decreased DENV-2 replication in the cell line. In contrast, the RNAi-mediated suppression of l(2)efl gene products resulted in enhanced DENV-2 replication, but this enhancement occurred only if multiple l(2)efl genes were suppressed. l(2)efl homologs induce the phosphorylation of eukaryotic initiation factor 2\u03b1 (eIF2\u03b1) in the fruit fly Drosophila melanogaster, and we confirmed this finding in the cell line. However, the mechanism by which l(2)efl phosphorylates eIF2\u03b1 remains unclear. We conclude that l(2)efl encodes a potential anti-dengue protein in the vector mosquito.<\/jats:p>","DOI":"10.3390\/ijms21207520","type":"journal-article","created":{"date-parts":[[2020,10,13]],"date-time":"2020-10-13T21:48:38Z","timestamp":1602625718000},"page":"7520","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["The Lethal(2)-Essential-for-Life [L(2)EFL] Gene Family Modulates Dengue Virus Infection in Aedes aegypti"],"prefix":"10.3390","volume":"21","author":[{"given":"Lucky R.","family":"Runtuwene","sequence":"first","affiliation":[{"name":"Department of Infectious Disease Control, Faculty of Medicine, Oita University, Oita 879-5593, Japan"},{"name":"Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan"},{"name":"AIDS Research Centre, National Institute of Infectious Diseases, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichi","family":"Kawashima","sequence":"additional","affiliation":[{"name":"Database Center for Life Science, Joint Support-Center for Data Science Research, Research Organization of Information and Systems, 178-4-4 Wakashiba, Kashiwa, Chiba 277-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor D.","family":"Pijoh","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Sam Ratulangi University, Kampus Unsrat, Bahu Manado 95-115, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef S. B.","family":"Tuda","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Sam Ratulangi University, Kampus Unsrat, Bahu Manado 95-115, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoko","family":"Hayashida","sequence":"additional","affiliation":[{"name":"Division of Collaboration and Education, Research Center for Zoonosis Control, Hokkaido University, North 20, West 10 Kita-ku, Sapporo, Hokkaido 001-0020, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junya","family":"Yamagishi","sequence":"additional","affiliation":[{"name":"Division of Collaboration and Education, Research Center for Zoonosis Control, Hokkaido University, North 20, West 10 Kita-ku, Sapporo, Hokkaido 001-0020, Japan"},{"name":"Global Station for Zoonosis Control, GI-CoRE, Hokkaido University, North 20, West 10 Kita-ku, Sapporo, Hokkaido 001-0020, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"Division of Collaboration and Education, Research Center for Zoonosis Control, Hokkaido University, North 20, West 10 Kita-ku, Sapporo, Hokkaido 001-0020, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoko","family":"Nishiyama","sequence":"additional","affiliation":[{"name":"Laboratory of Zoonotic Diseases, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1607-2175","authenticated-orcid":false,"given":"Michihito","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, North 20, West 10 Kita-ku, Sapporo, Hokkaido 001-0020, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9910-3912","authenticated-orcid":false,"given":"Yasuko","family":"Orba","sequence":"additional","affiliation":[{"name":"Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, North 20, West 10 Kita-ku, Sapporo, Hokkaido 001-0020, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2569-2755","authenticated-orcid":false,"given":"Hirofumi","family":"Sawa","sequence":"additional","affiliation":[{"name":"Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, North 20, West 10 Kita-ku, Sapporo, Hokkaido 001-0020, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2491-6163","authenticated-orcid":false,"given":"Tomohiko","family":"Takasaki","sequence":"additional","affiliation":[{"name":"National Institute of Infectious Diseases, Tokyo 162-8640, Japan"},{"name":"Kanagawa Prefectural Institute of Public Health, Kanagawa 253-0087, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5577-3308","authenticated-orcid":false,"given":"Anthony A.","family":"James","sequence":"additional","affiliation":[{"name":"Departments of Microbiology &amp; Molecular Genetics and Molecular Biology &amp; Biochemistry, University of California, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease Control, Faculty of Medicine, Oita University, Oita 879-5593, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1468-703X","authenticated-orcid":false,"given":"Yuki","family":"Eshita","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease Control, Faculty of Medicine, Oita University, Oita 879-5593, Japan"},{"name":"Departments of Medical Entomology, Faculty of Tropical Medicine, Mahidol University, 420\/6 Ratchawithi Road, Rajathewi, Bangkok 10400, Thailand"},{"name":"Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan"},{"name":"Hokudai Center for Zoonosis Control in Zambia, Research Center for Zoonosis Control, Hokkaido University, North 20, West 10 Kita-ku, Sapporo, Hokkaido 001-0020, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/S0966-842X(01)02288-0","article-title":"Epidemic dengue\/dengue hemorrhagic fever as a public health, social and economic problem in the 21st century","volume":"10","author":"Gubler","year":"2002","journal-title":"Trends Microbiol."},{"key":"ref_2","unstructured":"World Health Organization (2009). Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control, WHO."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1128\/CMR.11.3.480","article-title":"Dengue and dengue hemorrhagic fever","volume":"11","author":"Gubler","year":"1998","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1016\/S0140-6736(12)61428-7","article-title":"Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: A randomised, controlled phase 2b trial","volume":"380","author":"Sabchareon","year":"2012","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"Bhatt","year":"2013","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Del Angel, R.M., and Valle, J.R. (2013). Dengue vaccines: Strongly sought but not a reality just yet. PLoS Pathog, 9.","DOI":"10.1371\/journal.ppat.1003551"},{"key":"ref_7","unstructured":"World Health Organization (2018, May 20). Updated Questions and Answers Related to Information Presented in the Sanofi Pasteur Press Release on 30 November 2017 with Regards to the Dengue Vaccine Dengvaxia\u00ae. Available online: http:\/\/www.who.int\/immunization\/diseases\/dengue\/q_and_a_dengue_vaccine_dengvaxia\/en\/."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Gubler, D.J., and Kuno, G. (1997). Surveillance and control of urban dengue vectors. Dengue and Dengue Hemorrhagic Fever, CAB International.","DOI":"10.1016\/B978-0-443-06668-9.50077-6"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.pt.2004.11.004","article-title":"Gene drive systems in mosquitoes: Rules of the road","volume":"21","author":"James","year":"2005","journal-title":"Trends Parasitol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4198","DOI":"10.1073\/pnas.0600479103","article-title":"Engineering RNA interference-based resistance to dengue virus type 2 in genetically modified Aedes aegypti","volume":"103","author":"Franz","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Behura, S.K., Gomez-Machorro, C., Harker, B.W., DeBruyn, B., Lovin, D.D., Hemme, R.R., Mori, A., Romero-Severson, J., and Severson, D.W. (2011). Global cross-talk of genes of the mosquito Aedes aegypti in response to dengue virus infection. PLoS Negl. Trop. Dis., 5.","DOI":"10.1371\/journal.pntd.0001385"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Bonizzoni, M., Dunn, W.A., Campbell, C.L., Olson, K.E., Marinotti, O., and James, A.A. (2012). Complex modulation of the Aedes aegypti transcriptome in response to dengue virus infection. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0050512"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Guo, X., Xu, Y., Bian, G., Pike, A.D., Xie, Y., and Xi, Z. (2010). Response of the mosquito protein interaction network to dengue infection. BMC Genom., 11.","DOI":"10.1186\/1471-2164-11-380"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Doolittle, M.J., and Gomez, S.M. (2011). Mapping protein interactions between dengue virus and its human and insect hosts. PLoS Negl. Trop. Dis., 5.","DOI":"10.1371\/journal.pntd.0000954"},{"key":"ref_15","first-page":"115","article-title":"Protein profiles of dengue-infected Aedes aegypti (L)","volume":"33","author":"Lee","year":"2009","journal-title":"Dengue Bull."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Sim, S., and Dimopoulos, G. (2010). Dengue virus inhibits immune responses in Aedes aegypti cells. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010678"},{"key":"ref_17","first-page":"1","article-title":"Differential gene expression from midguts of refractory and susceptible lines of the mosquito, Aedes aegypti, infected with dengue-2 virus","volume":"10","author":"Lowenberger","year":"2010","journal-title":"J. Insect Sci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Sim, S., Ramirez, J.L., and Dimopoulos, G. (2012). Dengue virus infection of the Aedes aegypti salivary gland and chemosensory apparatus induces genes that modulate infection and blood-feeding behavior. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002631"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Xi, Z., Ramirez, J.L., and Dimopoulos, G. (2008). The Aedes aegypti toll pathway controls dengue virus infection. PLoS Pathog., 4.","DOI":"10.1371\/journal.ppat.1000098"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"17841","DOI":"10.1073\/pnas.0905006106","article-title":"An evolutionary conserved function of the JAK-STAT pathway in anti-dengue defense","volume":"106","author":"Sim","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/1756-3305-7-143","article-title":"Dengue transmission model by means of viremic adult immuno-competent mouse","volume":"7","author":"Runtuwene","year":"2014","journal-title":"Parasit. Vectors"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1126\/science.1138878","article-title":"Genome sequence of Aedes aegypti, a major arbovirus vector","volume":"316","author":"Nene","year":"2007","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4738","DOI":"10.1128\/JVI.73.6.4738-4747.1999","article-title":"Dengue virus structural differences that correlate with pathogenesis","volume":"73","author":"Leitmeyer","year":"1999","journal-title":"J. Virol."},{"key":"ref_24","first-page":"266","article-title":"Molecular evolution, distribution and genetic relationship among the dengue 2 viruses isolated from different clinical severity","volume":"31","author":"Pandey","year":"2000","journal-title":"Southeast Asian J. Trop. Med. Public Health"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Salazar, M.I., Richardson, J.H., S\u00e1nchez-Vargas, I., Olson, K.E., and Beaty, B.J. (2007). Dengue virus type 2: Replication and tropisms in orally infected Aedes aegypti mosquitoes. BMC Microbiol., 7.","DOI":"10.1186\/1471-2180-7-9"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"The Gene Ontology Consortium (2000). Gene ontology: Tool for the unification of biology. Nat. Genet., 25, 25\u201329.","DOI":"10.1038\/75556"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Colpitts, T.M., Barthel, S., Wang, P., and Fikrig, E. (2011). Dengue virus capsid protein binds core histones and inhibits nucleosome formation in human liver cells. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024365"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1603\/033.046.0312","article-title":"Identification of genes differentially expressed during heat shock treatment in Aedes aegypti","volume":"46","author":"Zhao","year":"2009","journal-title":"J. Med. Entomol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"37811","DOI":"10.1074\/jbc.M110.127498","article-title":"Identification of the Drosophila ortholog of HSPB8: Implication of HSPB8 loss of function in protein folding diseases","volume":"285","author":"Carra","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1002\/jmv.1890440111","article-title":"Rapid detection of virus genome from imported dengue fever and dengue hemorrhagic fever patients by direct polymerase chain reaction","volume":"44","author":"Morita","year":"1994","journal-title":"J. Med. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1093\/nar\/gkn857","article-title":"VectorBase: A data resource for invertebrate vector genomics","volume":"37","author":"Lawson","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1093\/bioinformatics\/btp120","article-title":"TopHat: Discovering splice junctions with RNA-Seq","volume":"25","author":"Trapnell","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/nbt.1621","article-title":"Transcript assembly and abundance estimation from RNA-seq reveals thousands of new transcripts and switching among isoforms","volume":"28","author":"Trapnell","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative CT method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_35","unstructured":"Social Science Statistics (2014, June 18). n.d. Spearman\u2019s Rho Calculator. Available online: http:\/\/www.socscistatistics.com\/tests\/spearman\/default2.aspx."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Colpitts, T.M., Cox, J., Vanlandingham, D.L., Feitosa, F.M., Cheng, G., Kurscheid, S., Wang, P., Krishnan, M.N., Higgs, S., and Fikrig, E. (2011). Alterations in the Aedes aegypti transcriptome during infection with West Nile, dengue and yellow fever viruses. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002189"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"David, J.-P., Coissac, E., Melodelima, C., Poupardin, R., Riaz, M.A., Chandor-Proust, A., and Reynaud, S. (2010). Transcriptome response to pollutants and insecticides in the dengue vector Aedes aegypti using next-generation sequencing technology. BMC Genom., 11.","DOI":"10.1186\/1471-2164-11-216"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6112","DOI":"10.1038\/sj.onc.1203127","article-title":"PKR; a sentinel kinase for cellular stress","volume":"18","author":"Williams","year":"1999","journal-title":"Oncogene"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"13512","DOI":"10.1074\/jbc.M501156200","article-title":"Inhibition of host and viral translation during vesicular stomatitis virus infection: eIF2 is responsible for the inhibition of viral but not host translation","volume":"280","author":"Connor","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"431","DOI":"10.4269\/ajtmh.13-0412","article-title":"Effect of Dengue-2 Virus in the Salivary Glands of Aedes aegypti Mosquitoes","volume":"90","author":"Chisenhall","year":"2014","journal-title":"Am. J. Trop. Med. Hyg."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/20\/7520\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:20:00Z","timestamp":1760178000000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/20\/7520"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,12]]},"references-count":40,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["ijms21207520"],"URL":"https:\/\/doi.org\/10.3390\/ijms21207520","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,12]]}}}