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Engineered resistance to Zika virus in transgenic Ae. aegypti expressing a polycistronic cluster of synthetic miRNAs

Buchman, Anna and Gamez, Stephanie and Li, Ming and Antoshechkin, Igor and Lee, Shin-Hang and Wang, Shin-Wei and Chen, Chun-Hong and Klein, Melissa J. and Duchmemin, Jean-Bernard and Paradkar, Prasad N. and Akbari, Omar S. (2018) Engineered resistance to Zika virus in transgenic Ae. aegypti expressing a polycistronic cluster of synthetic miRNAs. . (Unpublished) http://resolver.caltech.edu/CaltechAUTHORS:20181030-080547581

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Abstract

Recent Zika virus (ZIKV) outbreaks have highlighted the necessity for development of novel vector control strategies to combat arboviral transmission, including genetic versions of the sterile insect technique, artificial infection with Wolbachia to reduce population size and/or vectoring competency, and gene drive based methods. Here, we describe the development of mosquitoes synthetically engineered to impede vector competence to ZIKV. We demonstrate that a polycistronic cluster of engineered microRNAs (miRNAs) targeting ZIKV is expressed and fully processed following a blood meal in Ae. aegypti, ensuring the formation of mature synthetic miRNAs in the midgut where ZIKV resides in the early stages of infection. Critically, we demonstrate that engineered Ae. aegypti mosquitoes harboring the anti-ZIKV transgene have significantly reduced viral infection, dissemination, and transmission rates of ZIKV. Taken together, these compelling results provide a promising path forward for development of effective genetic-based ZIKV control strategies, which could potentially be extended to curtail other arboviruses.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/344697DOIDiscussion Paper
ORCID:
AuthorORCID
Buchman, Anna0000-0002-8775-6147
Antoshechkin, Igor0000-0002-9934-3040
Akbari, Omar S.0000-0002-6853-9884
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license. bioRxiv preprint first posted online Jun. 12, 2018. This work was supported in part by an NIH-K22 Career Transition award (5K22AI113060), an NIH Exploratory/Developmental Research Grant Award (1R21AI123937) awarded to O.S.A and CSIRO internal funding to P.N.P. We thank Prof. Robert Tesh and Dr. Nikos Vasilakis (UTMB, Texas) for providing the ZIKV FSS13025 and PRVABC59 strains and Lee Trinidad for preparing viral stocks. We thank Christian Bowman for helping with the inverse PCR. We also thank Prof. Scott O’Neill (Institute of Vector Borne Diseases, Monash University, Australia) and World Mosquito Program for providing Wolbachia infected mosquito eggs. Finally, we thank Dr. Guann-Yi Yu (NTU, Taiwan) for providing the Stat -/- mice used in this study. Author Contributions: A.B., P.N.P., and O.S.A conceived and designed experiments. A.B., S.G, M.L. performed all molecular and genetic experiments. I.A performed sequencing and bioinformatic analysis. M.J.K., J.B.D and P.N.P. performed and analyzed data for ZIKV mosquito challenge assays. S.H.L., S.W.W., and C.H.C performed and analyzed data for in vivo mouse model ZIKV mosquito challenge assays. All authors contributed to the writing and approved the final manuscript. Competing interests: A.B. and O.S.A have submitted a provisional patent application on this technology. All other authors declare no competing financial interests. Data Availability Statement: All sequencing data associated with this study are available from NCBI sequence read archive (SRA) accession ID: SRP150144; BioProject ID: PRJNA475410. Complete annotated plasmid sequence and DNA is publically available at Addgene (plasmid #104968). Transgenic mosquitoes will be made available by corresponding author upon request.
Funders:
Funding AgencyGrant Number
NIH5K22AI113060
NIH1R21AI123937
Commonwealth Scientific and Industrial Research Organisation (CSIRO)UNSPECIFIED
Record Number:CaltechAUTHORS:20181030-080547581
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20181030-080547581
Official Citation:Engineered resistance to Zika virus in transgenic Ae. aegypti expressing a polycistronic cluster of synthetic miRNAs. Anna Buchman, Stephanie Gamez, Ming Li, Igor Antoshechkin, hin-Hang Lee, Shin-Wei Wang, Chun-Hong Chen, Melissa J Klein, Jean-Bernard Duchmemin, Prasad N. Paradkar, Omar S Akbari. bioRxiv 344697; doi: https://doi.org/10.1101/344697
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90488
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:30 Oct 2018 17:07
Last Modified:30 Oct 2018 17:07

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