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Insects 2019, 10(2), 46; https://doi.org/10.3390/insects10020046

Homologs of Human Dengue-Resistance Genes, FKBP1B and ATCAY, Confer Antiviral Resistance in Aedes aegypti Mosquitoes

1
Emerging Pathogens Institute and the Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA
2
Florida Medical Entomology Laboratory, Department of Nematology and Entomology, Institute of Food and Agricultural Sciences, University of Florida, Vero Beach, FL 32962, USA
3
Department of Entomology, College of Agriculture, Kansas State University, Manhattan, KS 66506, USA
4
Department of Agricultural Biology, College of Agriculture and Life Sciences, Chonnam National University, Gwang-ju 500-757, Korea
5
Department of Microbiology, Boston University School of Medicine, National Emerging Infectious Diseases Laboratories, Boston, MA 02118, USA
6
Access Bio, Inc., Somerset, NJ 08873, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Received: 1 September 2018 / Revised: 26 January 2019 / Accepted: 29 January 2019 / Published: 2 February 2019
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Abstract

Dengue virus (DENV) is transmitted by mosquitoes and is a major public health concern. The study of innate mosquito defense mechanisms against DENV have revealed crucial roles for the Toll, Imd, JAK-STAT, and RNAi pathways in mediating DENV in the mosquito. Often overlooked in such studies is the role of intrinsic cellular defense mechanisms that we hypothesize to work in concert with the classical immune pathways to affect organismal defense. Our understanding of the molecular interaction of DENV with mosquito host cells is limited, and we propose to expand upon the recent results from a genome-scale, small interfering RNA (siRNA)-based study that identified mammalian host proteins associated with resistance to dengue/West Nile virus (DENV/WNV) infection. The study identified 22 human DENV/WNV resistance genes (DVR), and we hypothesized that a subset would be functionally conserved in Aedes aegypti mosquitoes, imparting cellular defense against flaviviruses in this species. We identified 12 homologs of 22 human DVR genes in the Ae. aegypti genome. To evaluate their possible role in cellular resistance/antiviral defense against DENV, we used siRNA silencing targeted against each of the 12 homologs in an Ae. aegypti cell line (Aag2) infected with DENV2 and identified that silencing of the two candidates, AeFKBP1 and AeATCAY, homologs of human FKBP1B and ATCAY, were associated with a viral increase. We then used dsRNA to silence each of the two genes in adult mosquitoes to validate the observed antiviral functions in vivo. Depletion of AeFKBP1 or AeATCAY increased viral dissemination through the mosquito at 14 days post-infection. Our results demonstrated that AeFKBP1 and AeATCAY mediate resistance to DENV akin to what has been described for their homologs in humans. AeFKBP1 and AeATCAY provide a rare opportunity to elucidate a DENV-resistance mechanism that may be evolutionarily conserved between humans and Ae. aegypti. View Full-Text
Keywords: Aedes aegypti; dengue virus type 2; anti-dengue viral gene; AeFKBP1; AeATCAY; RNA interference Aedes aegypti; dengue virus type 2; anti-dengue viral gene; AeFKBP1; AeATCAY; RNA interference
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Kang, S.; Shin, D.; Mathias, D.K.; Londono-Renteria, B.; Noh, M.Y.; Colpitts, T.M.; Dinglasan, R.R.; Han, Y.S.; Hong, Y.S. Homologs of Human Dengue-Resistance Genes, FKBP1B and ATCAY, Confer Antiviral Resistance in Aedes aegypti Mosquitoes. Insects 2019, 10, 46.

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