Dengue and Zika RNA-RNA interactomes reveal virus permissive and restrictive factors in human cells.
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ABSTRACT:
PROVIDER: PRJNA736235 | ENA |
REPOSITORIES: ENA
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Project description:Identifying host factors is key to understanding RNA virus pathogenicity. Besides proteins, RNAs can interact with virus genomes to impact replication. Here, we used proximity ligation sequencing to identify virus-host RNA interactions for four strains of Zika virus (ZIKV) and one strain of dengue virus (DENV-1) in human cells. We found hundreds of coding and non-coding RNAs that bind to DENV and ZIKV viruses. Host RNAs tend to bind to single-stranded regions along the virus genomes and the binding is primarily driven by hybridization energetics. We observed that virus interacting host RNAs tend to be downregulated upon virus infection and identified a conserved set of virus responders that binds to most DENV and ZIKV. Knockdown of several short non-coding RNAs, including miR19a-3p, SCARNA2 and 7SK RNA resulted in a decrease in virus growth, suggesting that they act as virus permissive factors. In addition, the 3’UTR of DYNLT1 mRNA acts as a virus restrictive factor by binding to the conserved dumbbell region on DENV and ZIKV 3’UTR to decrease virus replication. This study demonstrates that host RNAs in themselves can impact virus growth in permissive and restrictive ways, expanding our understanding of host factors and RNA-based gene regulation during virus pathogenesis.
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Project description:Dengue and Zika are closely related members of the Flaviviridae family of positive, single-stranded RNA viruses and are of global clinical importance. These viruses utilize an 11kb RNA genome for translation and replication, and much remains to be learnt about how the entire genome folds to enable virus function. Here, we performed high throughput RNA secondary structure and pair-wise interaction mapping on four dengue serotypes and four Zika strains within their virus particles. We identified structures that are associated with translation pausing, and are evolutionary conserved by integrating synonymous mutation rates into our analysis. Genome-wide interaction mapping revealed alternative structures, as well as extensive long-range RNA interactions – including the known circularization signals– within the virus particles. Many of these long-range interactions are conserved across the viruses and/or clustered into “hubs” that are shown to be functionally important. This comprehensive structural resource of dengue and Zika viruses reveals that viral genome organization is much more complex than previously appreciated and deepens our understanding of the molecular basis for viral pathogenesis.
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Project description:Dengue and Zika are two mosquito-borne diseases of great concern, affecting mainly the tropical and subtropical regions worldwide. The arrival of Zika virus (ZIKV) in dengue virus (DENV) endemic areas imposed challenges for differential diagnosis and the development of candidate vaccines. The use of peptides has shown great potential to achieve these goals. We aimed to identify the linear epitope profile recognized by the serum samples of dengue and Zika patients in the E and NS1 proteins of DENV and ZIKV to select peptides with the potential for the development of diagnostic tests and vaccines. Analysis of a peptide microarray platform with serum samples of dengue and Zika patients demonstrated that the epitopes were evenly distributed across the entire viral proteins, showing no preference for particular regions. However, several epitopes were within epitope hot spots constituted by clusters of peptides recognized in more than 30% of the sub-arrays analyzed with individual or pools of serum samples. The serum samples of dengue and Zika patients showed a high level of cross-reaction for epitopes in the DENV and ZIKV proteins. Analysis of an additional peptide microarray platform containing selected peptides based on the results of the first screening showed that three peptides (DENV: TQGEPSLNEEQDKRF and TQTVGPWHLGKLEID; ZIKV: LELDPPFGDSYIVIG), highly specific for their cognate viruses (p<0.05), were within the epitope hot spots; however, these peptides showed low detection rates (32.5, 35.0, and 28.6%, respectively). We also found two peptides (DENV: WEVEDYGFGVFTTNI and LELDFDLCEGTTVVV) in the epitope hot spots detected by both dengue and Zika patients with similarly high rates (arbitrary detection rate cut-off threshold of ≥40%). The epitope hot spots harbor several immunodominant epitopes recognized by a higher number of individuals when compared to the 15 aa sequence peptides. Therefore, the entire epitope hot spots, spanning up to ~30 aa, would have more potential than peptides of only 15 aa to serve as antigens in diagnostic tests and vaccine developments.
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Project description:Dengue and Zika are two mosquito-borne diseases of great concern, affecting mainly the tropical and subtropical regions worldwide. The arrival of Zika virus (ZIKV) in dengue virus (DENV) endemic areas imposed challenges for differential diagnosis and the development of candidate vaccines. The use of peptides has shown great potential to achieve these goals. We aimed to identify the linear epitope profile recognized by the serum samples of dengue and Zika patients in the E and NS1 proteins of DENV and ZIKV to select peptides with the potential for the development of diagnostic tests and vaccines. Analysis of a peptide microarray platform with serum samples of dengue and Zika patients demonstrated that the epitopes were evenly distributed across the entire viral proteins, showing no preference for particular regions. However, several epitopes were within epitope hot spots constituted by clusters of peptides recognized in more than 30% of the sub-arrays analyzed with individual or pools of serum samples. The serum samples of dengue and Zika patients showed a high level of cross-reaction for epitopes in the DENV and ZIKV proteins. Analysis of an additional peptide microarray platform containing selected peptides based on the results of the first screening showed that three peptides (DENV: TQGEPSLNEEQDKRF and TQTVGPWHLGKLEID; ZIKV: LELDPPFGDSYIVIG), highly specific for their cognate viruses (p<0.05), were within the epitope hot spots; however, these peptides showed low detection rates (32.5, 35.0, and 28.6%, respectively). We also found two peptides (DENV: WEVEDYGFGVFTTNI and LELDFDLCEGTTVVV) in the epitope hot spots detected by both dengue and Zika patients with similarly high rates (arbitrary detection rate cut-off threshold of ≥40%). The epitope hot spots harbor several immunodominant epitopes recognized by a higher number of individuals when compared to the 15 aa sequence peptides. Therefore, the entire epitope hot spots, spanning up to ~30 aa, would have more potential than peptides of only 15 aa to serve as antigens in diagnostic tests and vaccine developments.
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Project description:Flaviviruses, including Dengue and Zika, are widespread human pathogens; however, no broadly active therapeutics exist to fight infection. Recently, remodeling of endoplasmic reticulum (ER) proteostasis by pharmacologic regulators, such as compound 147, was shown to correct pathologic ER imbalances associated with protein misfolding diseases. Here, we establish a new activity of compound 147 as an effective host-centered antiviral agent against flaviviruses. Compound 147 reduces infection by attenuating the infectivity of secreted virions without causing toxicity in host cells. 147 is a preferential activator of the ATF6 pathway of the ER unfolded protein response, which requires targeting of cysteine residues primarily on protein disulfide isomerases (PDIs). We find that the antiviral activity of 147 is independent of ATF6 induction but does require modification of reactive thiols on protein targets. Targeting PDIs and additional non-PDI targets using RNAi and other small molecule inhibitors was unable to recapitulate the antiviral effects, suggesting a unique polypharmacology may mediate the activity. Importantly, 147 can impair infection of multiple strains of Dengue and Zika virus, indicating that it is suitable as a broad-spectrum antiviral agent.
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