The Aedes Aegypti SiRNA Pathway Mediates Broad-spectrum Defense Against Human Pathogenic Viruses and Modulates Antibacterial and Antifungal Defenses

Overview

Journal PLoS Biol

Specialty Biology

Date 2022 Jun 9

PMID 35679279

Authors

Yuemei Dong

Shengzhang Dong

Nahid Borhani Dizaji

Natalie Rutkowski

Tyler Pohlenz

Kevin Myles

George Dimopoulos

Affiliations

Soon will be listed here.

Abstract

The mosquito's innate immune system defends against a variety of pathogens, and the conserved siRNA pathway plays a central role in the control of viral infections. Here, we show that transgenic overexpression of Dicer2 (Dcr2) or R2d2 resulted in an accumulation of 21-nucleotide viral sequences that was accompanied by a significant suppression of dengue virus (DENV), Zika virus (ZIKV), and chikungunya virus (CHIKV) replication, thus indicating the broad-spectrum antiviral response mediated by the siRNA pathway that can be applied for the development of novel arbovirus control strategies. Interestingly, overexpression of Dcr2 or R2d2 regulated the mRNA abundance of a variety of antimicrobial immune genes, pointing to additional functions of DCR2 and R2D2 as well as cross-talk between the siRNA pathway and other immune pathways. Accordingly, transgenic overexpression of Dcr2 or R2d2 resulted in a lesser proliferation of the midgut microbiota and increased resistance to bacterial and fungal infections.

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References

Galiana-Arnoux D, Dostert C, Schneemann A, Hoffmann J, Imler J . Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila. Nat Immunol. 2006; 7(6):590-7. DOI: 10.1038/ni1335. View

Marques J, Kim K, Wu P, Alleyne T, Jafari N, Carthew R . Loqs and R2D2 act sequentially in the siRNA pathway in Drosophila. Nat Struct Mol Biol. 2009; 17(1):24-30. PMC: 2919300. DOI: 10.1038/nsmb.1735. View

Weaver S . Evolutionary influences in arboviral disease. Curr Top Microbiol Immunol. 2006; 299:285-314. PMC: 7120121. DOI: 10.1007/3-540-26397-7_10. View

Vasilakis N, Tesh R . Insect-specific viruses and their potential impact on arbovirus transmission. Curr Opin Virol. 2015; 15:69-74. PMC: 4688193. DOI: 10.1016/j.coviro.2015.08.007. View

Coll O, Guitart T, Villalba A, Papin C, Simonelig M, Gebauer F . Dicer-2 promotes mRNA activation through cytoplasmic polyadenylation. RNA. 2018; 24(4):529-539. PMC: 5855953. DOI: 10.1261/rna.065417.117. View

Adelman Z, Jasinskiene N, Onal S, Juhn J, Ashikyan A, Salampessy M . nanos gene control DNA mediates developmentally regulated transposition in the yellow fever mosquito Aedes aegypti. Proc Natl Acad Sci U S A. 2007; 104(24):9970-5. PMC: 1891237. DOI: 10.1073/pnas.0701515104. View

Li M, Yang T, Kandul N, Bui M, Gamez S, Raban R . Development of a confinable gene drive system in the human disease vector . Elife. 2020; 9. PMC: 6974361. DOI: 10.7554/eLife.51701. View

Franz A, Jasinskiene N, Sanchez-Vargas I, Isaacs A, Smith M, Khoo C . Comparison of transgene expression in Aedes aegypti generated by mariner Mos1 transposition and ΦC31 site-directed recombination. Insect Mol Biol. 2011; 20(5):587-98. PMC: 3556457. DOI: 10.1111/j.1365-2583.2011.01089.x. View

Wang Z, Wu D, Liu Y, Xia X, Gong W, Qiu Y . Drosophila Dicer-2 has an RNA interference-independent function that modulates Toll immune signaling. Sci Adv. 2015; 1(9):e1500228. PMC: 4646792. DOI: 10.1126/sciadv.1500228. View

10.

Tjaden N, Thomas S, Fischer D, Beierkuhnlein C . Extrinsic Incubation Period of Dengue: Knowledge, Backlog, and Applications of Temperature Dependence. PLoS Negl Trop Dis. 2013; 7(6):e2207. PMC: 3694834. DOI: 10.1371/journal.pntd.0002207. View

11.

Cheng G, Liu Y, Wang P, Xiao X . Mosquito Defense Strategies against Viral Infection. Trends Parasitol. 2015; 32(3):177-186. PMC: 4767563. DOI: 10.1016/j.pt.2015.09.009. View

12.

Ma L, Liu L, Zhao Y, Yang L, Chen C, Li Z . JNK pathway plays a key role in the immune system of the pea aphid and is regulated by microRNA-184. PLoS Pathog. 2020; 16(6):e1008627. PMC: 7343183. DOI: 10.1371/journal.ppat.1008627. View

13.

Travanty E, Adelman Z, Franz A, Keene K, Beaty B, Blair C . Using RNA interference to develop dengue virus resistance in genetically modified Aedes aegypti. Insect Biochem Mol Biol. 2004; 34(7):607-13. DOI: 10.1016/j.ibmb.2004.03.013. View

14.

Moreira L, Edwards M, Adhami F, Jasinskiene N, James A, Jacobs-Lorena M . Robust gut-specific gene expression in transgenic Aedes aegypti mosquitoes. Proc Natl Acad Sci U S A. 2000; 97(20):10895-8. PMC: 27120. DOI: 10.1073/pnas.97.20.10895. View

15.

Kokoza V, Ahmed A, Cho W, Jasinskiene N, James A, Raikhel A . Engineering blood meal-activated systemic immunity in the yellow fever mosquito, Aedes aegypti. Proc Natl Acad Sci U S A. 2000; 97(16):9144-9. PMC: 16836. DOI: 10.1073/pnas.160258197. View

16.

Langmead B, Trapnell C, Pop M, Salzberg S . Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009; 10(3):R25. PMC: 2690996. DOI: 10.1186/gb-2009-10-3-r25. View

17.

Sarinay Cenik E, Fukunaga R, Lu G, Dutcher R, Wang Y, Hall T . Phosphate and R2D2 restrict the substrate specificity of Dicer-2, an ATP-driven ribonuclease. Mol Cell. 2011; 42(2):172-84. PMC: 3115569. DOI: 10.1016/j.molcel.2011.03.002. View

18.

Dong Y, Simoes M, Marois E, Dimopoulos G . CRISPR/Cas9 -mediated gene knockout of Anopheles gambiae FREP1 suppresses malaria parasite infection. PLoS Pathog. 2018; 14(3):e1006898. PMC: 5843335. DOI: 10.1371/journal.ppat.1006898. View

19.

Tomari Y, Matranga C, Haley B, Martinez N, Zamore P . A protein sensor for siRNA asymmetry. Science. 2004; 306(5700):1377-80. DOI: 10.1126/science.1102755. View

20.

Williams A, Sanchez-Vargas I, Reid W, Lin J, Franz A, Olson K . The Antiviral Small-Interfering RNA Pathway Induces Zika Virus Resistance in Transgenic . Viruses. 2020; 12(11). PMC: 7692394. DOI: 10.3390/v12111231. View