RNA Structure Duplication in the Dengue Virus 3′ UTR: Redundancy or Host Specificity?

Abstract

Flaviviruses constitute the most relevant group of arthropod-transmitted viruses, including important human pathogens such as the dengue, Zika, yellow fever, and West Nile viruses. The natural alternation of these viruses between vertebrate and invertebrate hosts shapes the viral genome population, which leads to selection of different viral variants with potential implications for epidemiological fitness and pathogenesis. However, the selective forces and mechanisms acting on the viral RNA during host adaptation are still largely unknown. Here, we found that two almost identical tandem RNA structures present at the viral 3′ untranslated region are under different selective pressures in the two hosts. Mechanistic studies indicated that the two RNA elements, known as dumbbells, contain sequences that overlap essential RNA cyclization elements involved in viral RNA synthesis. The data support a model in which the duplicated RNA structures differentially evolved to accommodate distinct functions for viral replication in the two hosts.

Structural landscape of the complete genomes of Dengue serotypes and other viral hemorrhagic fevers

“…The genomes of viral hemorrhagic fevers show a high level of secondary structure, especially in the UTR regions 14,16 . This secondary structure is thought to be needed for different viral mechanisms, such as packaging and egression [11][12][13] .…”

“…The secondary structure of RNA viruses is fundamental for many viral functions, from encapsidation to egression from the cell and host defence [11][12][13] . Specific structures in the UTRs were found to be functional, for example, in Dengue, but also in HIV and coronaviruses 11,14,15 . Other structural regions, including the 3' UTR, were found conserved not only in Dengue serotypes but also between Dengue and Zika 16 .…”

Flavors of Flaviviral RNA Structure: towards an Integrated View of RNA Function from Translation through Encapsidation

“…In addition to the aforementioned similarities between SLA and SL, the 3′‐UTR of mosquito‐borne flaviviruses contains near‐identical A2 and A3 dumbbells (Figure ), as well as structurally similar SLI and SLII elements. These pairings are not commonly seen in flaviviruses with no known vector, making it clear that such duplication almost certainly relates to host‐switching . With regard to the dumbbell pair, deletion of the DENV A2 sequence significantly reduced replication in mosquito cells, while the opposite effect was observed upon A3 deletion .…”

“…These pairings are not commonly seen in flaviviruses with no known vector, making it clear that such duplication almost certainly relates to host‐switching . With regard to the dumbbell pair, deletion of the DENV A2 sequence significantly reduced replication in mosquito cells, while the opposite effect was observed upon A3 deletion . When the experiment was performed in human cells, the trends held but were far less dramatic.…”

Functional RNA Structures in the 3’UTR of Tick-Borne, Insect-Specific and No-Known-Vector Flaviviruses

“…To achieve this resilience in host adaptation, RNA duplication strategies have been proposed as an evolutionary trait for MBFVs [19]. Tandem RNA structures within DENV 3’UTR are under different selective pressures in alternating hosts, suggesting the idea that duplicated RNA structures differentially evolved to accommodate specific functions in the two hosts [20]. Likewise, there is evidence for evolutionary pressure on maintaining the primary sequence of parts of duplicated RNA elements, as recently shown for flaviviral dumbbell (DB) elements in the context of finding a biophysical model for explaining a possible route for ZIKV-induced neurotropism [21].…”