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Cell Rep. 2019 Jan 15;26(3):529-535.e3. doi: 10.1016/j.celrep.2018.12.068.

A Role for the Insulin Receptor in the Suppression of Dengue Virus and Zika Virus in Wolbachia-Infected Mosquito Cells.

Author information

1
Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, VIC 3800, Australia. Electronic address: gholamreza.haqshenas@monash.edu.
2
School of Biological Sciences, Monash University, Clayton, VIC 3800, Australia.
3
CSIRO Health and Biosecurity, Australian Animal Health Laboratory, Geelong, VIC, Australia.
4
School of Biological Sciences, Monash University, Clayton, VIC 3800, Australia; Department of Entomology, Center for Infectious Disease Dynamics, Pennsylvania State University, University Park, PA 16802, USA. Electronic address: eam7@psu.edu.
5
Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, VIC 3800, Australia. Electronic address: christian.doerig@rmit.edu.au.

Abstract

Wolbachia-infected mosquitoes are refractory to super-infection with arthropod-borne pathogens, but the role of host cell signaling proteins in pathogen-blocking mechanisms remains to be elucidated. Here, we use an antibody microarray approach to provide a comprehensive picture of the signaling response of Aedes aegypti-derived cells to Wolbachia. This approach identifies the host cell insulin receptor as being downregulated by the bacterium. Furthermore, siRNA-mediated knockdown and treatment with a small-molecule inhibitor of the insulin receptor kinase concur to assign a crucial role for this enzyme in the replication of dengue and Zika viruses in cultured mosquito cells. Finally, we show that the production of Zika virus in Wolbachia-free live mosquitoes is impaired by treatment with the selective inhibitor mimicking Wolbachia infection. This study identifies Wolbachia-mediated downregulation of insulin receptor kinase activity as a mechanism contributing to the blocking of super-infection by arboviruses.

KEYWORDS:

Aedes aegypti; Dengue virus; Wolbachia; Zika virus; antibody microarray; cell signaling; insulin receptor; insulin receptor kinase inhibitor; mosquito; siRNA

PMID:
30650347
DOI:
10.1016/j.celrep.2018.12.068
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