title: Dengue virus RNA structure specialization facilitates host adaptation.
abstract: Many viral pathogens cycle between humans and insects. These viruses must have evolved strategies for rapid adaptation to different host environments. However, the mechanistic basis for the adaptation process remains poorly understood. To study the mosquito-human adaptation cycle, we examined changes in RNA structures of the dengue virus genome during host adaptation. Deep sequencing and RNA structure analysis, together with fitness evaluation, revealed a process of host specialization of RNA elements of the viral 3'UTR. Adaptation to mosquito or mammalian cells involved selection of different viral populations harvesting mutations in a single stem-loop structure. The host specialization of the identified RNA structure resulted in a significant viral fitness cost in the non-specialized host, posing a constraint during host switching. Sequence conservation analysis indicated that the identified host adaptable stem loop structure is duplicated in dengue and other mosquito-borne viruses. Interestingly, functional studies using recombinant viruses with single or double stem loops revealed that duplication of the RNA structure allows the virus to accommodate mutations beneficial in one host and deleterious in the other. Our findings reveal new concepts in adaptation of RNA viruses, in which host specialization of RNA structures results in high fitness in the adapted host, while RNA duplication confers robustness during host switching.
authors: Fundación Instituto Leloir-CONICET, Buenos Aires, Argentina.
authors: Sergio M
authors: SM
authors: Villordo
authors: Fundación Instituto Leloir-CONICET, Buenos Aires, Argentina.
authors: Claudia V
authors: CV
authors: Filomatori
authors: Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Irma
authors: I
authors: Sánchez-Vargas
authors: Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors: Carol D
authors: CD
authors: Blair
authors: Fundación Instituto Leloir-CONICET, Buenos Aires, Argentina.
authors: Andrea V
authors: AV
authors: Gamarnik
mesh_terms: D020413:3' Untranslated Regions; D000220:Adaptation, Biological / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D009033:Culicidae; D003716:Dengue Virus / Q000235:genetics*; D058507:Host Specificity / Q000235:genetics; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000737:chemistry* / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D012367:RNA, Viral
references: J Virol. 2011 Jun;85(11):5664-8
references: 21411525
references: Science. 2014 Apr 18;344(6181):307-10
references: 24744377
references: Virol J. 2013;10:3
references: 23282086
references: Cell Host Microbe. 2008 Dec 11;4(6):579-91
references: 19064258
references: J Virol. 2013 Aug;87(16):9365-72
references: 23760236
references: Algorithms Mol Biol. 2011 Nov 24;6:26
references: 22115189
references: Virology. 2005 Sep 1;339(2):200-12
references: 16002117
references: PLoS Pathog. 2014 Jul;10(7):e1004242
references: 24992036
references: Virology. 1997 Apr 14;230(2):300-8
references: 9143286
references: PLoS Pathog. 2009 Jun;5(6):e1000467
references: 19503824
references: Future Microbiol. 2013 Feb;8(2):155-76
references: 23374123
references: J Gen Virol. 2007 Aug;88(Pt 8):2214-22
references: 17622625
references: PLoS Pathog. 2013;9(8):e1003591
references: 24009512
references: J Gen Virol. 2006 Nov;87(Pt 11):3297-305
references: 17030864
references: J Mol Evol. 2002 Feb;54(2):156-65
references: 11821909
references: J Virol. 2012 Dec;86(24):13486-500
references: 23035235
references: Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2746-51
references: 24550303
references: Genes Dev. 2006 Aug 15;20(16):2238-49
references: 16882970
references: J Gen Virol. 2011 Apr;92(Pt 4):841-8
references: 21216984
references: J Biol Chem. 2011 Jun 24;286(25):22521-34
references: 21515677
references: Viruses. 2010 Dec;2(12):2594-617
references: 21994633
references: J Virol. 2012 Jan;86(2):1046-58
references: 22072762
references: Curr Opin Virol. 2011 Dec;1(6):643-8
references: 22440922
references: Science. 2001 May 11;292(5519):1109-12
references: 11352066
references: Viruses. 2011 Sep;3(9):1739-56
references: 21994804
references: Gene. 1992 Dec 15;122(2):281-8
references: 1336756
references: Nat Struct Biol. 1995 Feb;2(2):171-8
references: 7749921
references: Nucleic Acids Res. 2013 May;41(9):5075-89
references: 23531545
references: Adv Virus Res. 2007;69:203-48
references: 17222695
references: Nucleic Acids Res. 2012 Mar;40(5):2210-23
references: 22080551
references: Nat Protoc. 2006;1(3):1610-6
references: 17406453
references: PLoS One. 2012;7(1):e30861
references: 22292064
references: Antiviral Res. 2013 May;98(2):273-83
references: 23523552
references: Annu Rev Microbiol. 1997;51:151-78
references: 9343347
references: Pac Symp Biocomput. 2010;:69-79
references: 19908359
references: Acc Chem Res. 2011 Dec 20;44(12):1280-91
references: 21615079
references: Elife. 2014;3:e01892
references: 24692447
references: RNA Biol. 2011 Nov-Dec;8(6):1173-86
references: 21957497
references: Nucleic Acids Res. 2014 Aug;42(14):9436-46
references: 25053841