Dataset Information

Evolution of Subgenomic RNA Shapes Dengue Virus Adaptation and Epidemiological Fitness.

ABSTRACT: Changes in dengue virus (DENV) genome affect viral fitness both clinically and epidemiologically. Even in the 3' untranslated region (3' UTR), mutations could affect subgenomic flaviviral RNA (sfRNA) production and its affinity for host proteins, which are necessary for successful viral replication. Indeed, we recently showed that mutations in DENV2 3' UTR of epidemic strains increased sfRNA ability to bind host proteins and reduce interferon expression. However, whether 3' UTR differences shape the overall DENV evolution remains incompletely understood. Herein, we combined RNA phylogeny with phylogenetics to gain insights on sfRNA evolution. We found that sfRNA structures are under purifying selection and highly conserved despite sequence divergence. Only the second flaviviral nuclease-resistant RNA (fNR2) structure of DENV2 sfRNA has undergone strong positive selection. Epidemiological reports suggest that substitutions in fNR2 may drive DENV2 epidemiological fitness, possibly through sfRNA-protein interactions. Collectively, our findings indicate that 3' UTRs are important determinants of DENV fitness in human-mosquito cycles.

SUBMITTER: Finol E

PROVIDER: S-EPMC6545344 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Evolution of Subgenomic RNA Shapes Dengue Virus Adaptation and Epidemiological Fitness.

Finol Esteban E Ooi Eng Eong EE

iScience 20190516

Changes in dengue virus (DENV) genome affect viral fitness both clinically and epidemiologically. Even in the 3' untranslated region (3' UTR), mutations could affect subgenomic flaviviral RNA (sfRNA) production and its affinity for host proteins, which are necessary for successful viral replication. Indeed, we recently showed that mutations in DENV2 3' UTR of epidemic strains increased sfRNA ability to bind host proteins and reduce interferon expression. However, whether 3' UTR differences shape ...[more]

PMID: 31154208

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Project description:Dengue viruses (DENV) are expanding global pathogens that are transmitted through the bite of mosquitoes, mostly Aedes aegypti. As RNA viruses, DENV rely on RNA-binding proteins (RBPs) to complete their life cycle. Alternatively, RBPs can act as restriction factors that prevent DENV multiplication. While the importance of RBPs is well-supported in humans, there is a dearth of information about their influence on DENV transmission by mosquitoes. Such knowledge could be harnessed to design novel, effective interventions against DENV. Here, we successfully adapted RNA-affinity chromatography coupled with mass spectrometry-a technique initially developed in mammalian cells-to identify RBPs in Ae. aegypti cells. We identified fourteen RBPs interacting with DENV serotype 2 3'UTR, which is involved in the viral multiplication and produces subgenomic flaviviral RNA (sfRNA). We validated the RNA affinity results for two RBPs by confirming that AePur binds the 3'UTR, whereas AeStaufen interacts with both 3'UTR and sfRNA. Using in vivo functional evaluation, we determined that RBPs like AeRan, AeExoRNase, and AeRNase have pro-viral functions, whereas AeGTPase, AeAtu, and AePur have anti-viral functions in mosquitoes. Furthermore, we showed that human and mosquito Pur homologs have a shared affinity to DENV2 RNA, although the anti-viral effect is specific to the mosquito protein. Importantly, we revealed that AeStaufen mediates a reduction of gRNA and sfRNA copies in several mosquito tissues, including the salivary glands and that AeStaufen-mediated sfRNA reduction diminishes the concentration of transmission-enhancing sfRNA in saliva, thereby revealing AeStaufen's role in DENV transmission. By characterizing the first RBPs that associate with DENV2 3'UTR in mosquitoes, our study unravels new pro- and anti-viral targets for the design of novel therapeutic interventions as well as provides foundation for studying the role of RBPs in virus-vector interactions.

Dataset Information

Evolution of Subgenomic RNA Shapes Dengue Virus Adaptation and Epidemiological Fitness.

Publications

Evolution of Subgenomic RNA Shapes Dengue Virus Adaptation and Epidemiological Fitness.

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