title: Dengue subgenomic RNA binds TRIM25 to inhibit interferon expression for epidemiological fitness.
abstract: The global spread of dengue virus (DENV) infections has increased viral genetic diversity, some of which appears associated with greater epidemic potential. The mechanisms governing viral fitness in epidemiological settings, however, remain poorly defined. We identified a determinant of fitness in a foreign dominant (PR-2B) DENV serotype 2 (DENV-2) clade, which emerged during the 1994 epidemic in Puerto Rico and replaced an endemic (PR-1) DENV-2 clade. The PR-2B DENV-2 produced increased levels of subgenomic flavivirus RNA (sfRNA) relative to genomic RNA during replication. PR-2B sfRNA showed sequence-dependent binding to and prevention of tripartite motif 25 (TRIM25) deubiquitylation, which is critical for sustained and amplified retinoic acid-inducible gene 1 (RIG-I)-induced type I interferon expression. Our findings demonstrate a distinctive viral RNA-host protein interaction to evade the innate immune response for increased epidemiological fitness.
authors.affiliation: Program in Emerging Infectious Diseases, Duke-National University of Singapore Graduate Medical School, Singapore. Defence Medical and Environmental Research Institute, DSO National Laboratories, Singapore. Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Manokaran
authors.affiliation: Program in Emerging Infectious Diseases, Duke-National University of Singapore Graduate Medical School, Singapore. Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Swiss Tropical and Public Health Institute, Universität Basel, Switzerland.
authors.forename: Esteban
authors.initials: E
authors.lastname: Finol
authors.affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, USA.
authors.forename: Chunling
authors.initials: C
authors.lastname: Wang
authors.affiliation: Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Institute of Molecular and Cell Biology, Singapore.
authors.forename: Jayantha
authors.initials: J
authors.lastname: Gunaratne
authors.affiliation: Center for Infectious Diseases, The University of Texas School of Public Health, Houston, TX, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Bahl
authors.affiliation: Program in Emerging Infectious Diseases, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Eugenia Z
authors.initials: EZ
authors.lastname: Ong
authors.affiliation: Program in Emerging Infectious Diseases, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Hwee Cheng
authors.initials: HC
authors.lastname: Tan
authors.affiliation: Program in Emerging Infectious Diseases, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: October M
authors.initials: OM
authors.lastname: Sessions
authors.affiliation: Program in Emerging Infectious Diseases, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Ward
authors.affiliation: Program in Emerging Infectious Diseases, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Duane J
authors.initials: DJ
authors.lastname: Gubler
authors.affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Harris
authors.affiliation: Program in Emerging Infectious Diseases, Duke-National University of Singapore Graduate Medical School, Singapore. Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA. Department of Molecular Genetics and Microbiology and Center for RNA Biology, Duke University, Durham, NC, USA.
authors.forename: Mariano A
authors.initials: MA
authors.lastname: Garcia-Blanco
authors.affiliation: Program in Emerging Infectious Diseases, Duke-National University of Singapore Graduate Medical School, Singapore. Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Saw Swee Hock School of Public Health, National University of Singapore, Singapore. Singapore-Massachusetts Institute of Technology Alliance in Research and Technology Infectious Disease Interdisciplinary Research Group, Singapore. engeong.ooi@duke-nus.edu.sg.
authors.forename: Eng Eong
authors.initials: EE
authors.lastname: Ooi
mesh_terms: D000818:Animals; D044822:Biodiversity; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D003715:Dengue / Q000453:epidemiology / Q000276:immunology* / Q000821:virology*; D003716:Dengue Virus / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D011647:Puerto Rico / Q000453:epidemiology; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic; D014157:Transcription Factors / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D014709:Vero Cells; D014779:Virus Replication
chemical_list: D007370:Interferon Type I; D012367:RNA, Viral; D011971:Receptors, Immunologic; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; C084523:TRIM25 protein, human; D044767:Ubiquitin-Protein Ligases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases