Evolution of RNA Structures in the Flavivirus Genome

HORACIO M. PALLARES; JUAN M. CARBALLEDAS; LUANA DE BORBA; ANDREA V. GAMARNIK; FRANCO L. MARSICO; SERGIO M. VILLORDO

Killarney

Congreso; Positive-Strand RNA Viruses (Keystone Symposia); 2019

Flaviviruses are a diverse group ofviruses with wide distribution in nature. They can be divided into fourecological groups according to the hosts that they infect. The ones thatalternate between vertebrate and insects are mosquito or tick borne viruses(MBFV and TBFV, respectively), which include relevant emerging and re-emerginghuman pathogens. The other two groups infect either insects or vertebrates.Flavivirus genomes contain important information in RNA structures involved inviral replication, pathogenesis and alternation between vertebrate andinvertebrate species. Although a great deal has been learnt about RNA signals thatmodulate flavivirus infections, little is known about their mechanisms ofaction. We analyzed the function of RNA structures present in all flavivirusgenomes and the ones specifically associate to the ability of viruses toalternate between vertebrate and invertebrate hosts. We identified a number ofcommon RNA elements for flavivirus genome replication. These elements include:a) a promoter for polymerase binding and activity, with an absolute conservationof structural elements essential for promoter activity, and b) topologicallyconserved complementary sequences that mediate long range RNA-RNA interactionswith specific features for different viral groups. This pan-flavivirus analysissupports a unique mechanism of viral RNA synthesis. Regarding RNA structuresinvolved in host alternation, we studied RNA elements present in MBFVs andrelated insect specific flaviviruses (ISFVr). Two types of RNA elements thatare duplicated in MBFV, and in single copies in the ISFVr, are associated tohost adaptation. To investigate the role of these RNA elements, we usedrecombinant Zika and dengue viruses and found that manipulating the duplicatedRNA structures it is possible to block host alternation. The mechanism ofaction of each of the two pairs of duplicated elements is different, while oneis involved in counteracting host antiviral responses, the other onedifferently modulates genome cyclization and RNA replication in mosquito andhuman cells.<!-- /* Font Definitions */ @font-face{font-family:"Cambria Math";panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:roman;mso-font-pitch:variable;mso-font-signature:3 0 0 0 1 0;}@font-face{font-family:Calibri;panose-1:2 15 5 2 2 2 4 3 2 4;mso-font-charset:0;mso-generic-font-family:swiss;mso-font-pitch:variable;mso-font-signature:-536859905 -1073732485 9 0 511 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin-top:0cm;margin-right:0cm;margin-bottom:8.0pt;margin-left:0cm;line-height:107%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-size:11.0pt;mso-ansi-font-size:11.0pt;mso-bidi-font-size:11.0pt;font-family:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}.MsoPapDefault{mso-style-type:export-only;margin-bottom:8.0pt;line-height:107%;}size:612.0pt 792.0pt;margin:72.0pt 72.0pt 72.0pt 72.0pt;mso-header-margin:36.0pt;mso-footer-margin:36.0pt;mso-paper-source:0;}div.WordSection1{page:WordSection1;}