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Replication is the key barrier during the dual-host adaptation of mosquito-borne flaviviruses.

ABSTRACT: Mosquito-borne flaviviruses (MBFs) adapt to a dual-host transmission circle between mosquitoes and vertebrates. Dual-host affiliated insect-specific flaviviruses (dISFs), discovered from mosquitoes, are phylogenetically similar to MBFs but do not infect vertebrates. Thus, dISF–MBF chimeras could be an ideal model to study the dual-host adaptation of MBFs. Using the pseudoinfectious reporter virus particle and reverse genetics systems, we found dISFs entered vertebrate cells as efficiently as the MBFs but failed to initiate replication. Exchange of the untranslational regions (UTRs) of Donggang virus (DONV), a dISF, with those from Zika virus (ZIKV) rescued DONV replication in vertebrate cells, and critical secondary RNA structures were further mapped. Essential UTR-binding host factors were screened for ZIKV replication in vertebrate cells, displaying different binding patterns. Therefore, our data demonstrate a post-entry cross-species transmission mechanism of MBFs, while UTR-host interaction is critical for dual-host adaptation.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC8944775 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Replication is the key barrier during the dual-host adaptation of mosquito-borne flaviviruses.

Zhang Yanan Y Liang Dening D Yuan Fei F Yan Yiran Y Wang Zuoshu Z Liu Pan P Yu Qi Q Zhang Xing X Wang Xiangxi X Zheng Aihua A

Proceedings of the National Academy of Sciences of the United States of America 20220316 12

Mosquito-borne flaviviruses (MBFs) adapt to a dual-host transmission circle between mosquitoes and vertebrates. Dual-host affiliated insect-specific flaviviruses (dISFs), discovered from mosquitoes, are phylogenetically similar to MBFs but do not infect vertebrates. Thus, dISF–MBF chimeras could be an ideal model to study the dual-host adaptation of MBFs. Using the pseudoinfectious reporter virus particle and reverse genetics systems, we found dISFs entered vertebrate cells as efficiently as the ...[more]

PMID: 35294288

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Project description:Background/Objective: World Health Organization latest statistics state that 17% of infectious diseases are transmitted by vectors, causing more than 700,000 deaths each year. Particularly, dengue (DENV), Zika (ZIKV) and yellow fever (YFV) viral infections have generated international awareness due to their epidemic proportion and risks of international spread. In this framework, the repositioning strategy of Efavirenz (EFV) represents a key clinical feature to improve different antiviral therapies. Therefore, the development of Soluplus®-based nanomicelles (NMs) loaded with EFV (10 mg/mL) for optimized oral pharmacotherapy against ZIKV, DENV and YFV infections was investigated. Methods: EFV-NMs were obtained by an acetone diffusion technique. Micellar size and in vitro micellar interaction with mucin were assessed by dynamic light scattering. In vitro cytocompatibility was investigated in A549 and Vero cells and micellar in vitro antiviral activity against ZIKV, DENV and YFV was evaluated. In vivo oral bioavailability and histological studies were assessed in Wistar rats. Results: EFV encapsulation within Soluplus® NMs increased the drug's apparent aqueous solubility up to 4803-fold with a unimodal micellar size distribution and a micellar size of ~90 nm at 25 and 37 °C. Micellar in vitro interaction with mucin was also assessed in a pH range of 1.2-7.5 and its storage micellar physicochemical stability at 4 °C was confirmed over 2 years. In vitro cytocompatibility assays in A549 and Vero cells confirmed that EFV micellar dispersions resulted in safe nanoformulations. Interestingly, EFV-loaded NMs exhibited significantly higher in vitro antiviral activity compared with EFV solution for all the tested flaviviruses. In addition, the selectivity index (SI) values reveal that EFV-loaded NMs exhibited considerably more biological efficacy compared to EFV solution in A549 and Vero cell lines and for each viral infection (SI > 10). Further, the drug pharmacokinetics parameters were enhanced after the oral administration of EFV-loaded NMs, being biocompatible by not causing damage in the gastrointestinal segments. Conclusions: Overall, our EFV nanoformulation highlighted its potential as a novel drug delivery platform for optimized ZIKV, DENV and YFV antiviral therapy.

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Replication is the key barrier during the dual-host adaptation of mosquito-borne flaviviruses.

Publications

Replication is the key barrier during the dual-host adaptation of mosquito-borne flaviviruses.

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