Aedes aegypti is the main vector of dengue, Zika, yellow fever and chikungunya viruses, and is a model system for studies of other mosquitoes that vector arboviruses. Current strategies based on suppressing mosquito populations can be effective, but are expensive and require a robust public health infrastructure. The ability to introgress pathogen-resistance genes into mosquito populations has long been sought as a potential alternative for disrupting dengue or malaria transmission where funds and infrastructure are the limiting factors in effective mosquito control. The recent development of effective site-specific nucleases such as homing endonucleases and CRISPR/Cas9 advanced technical solutions to achieving such super- Mendelian introgression, however there are still problems associated with the dominance of end-joining processes preventing the integration and spread of transgenic sequences. In this project, we aim to better understand DNA repair choice in mosquitoes and develop strategies to increase rates of homology-based repair following double-stranded DNA break induction.
In Aim1 we will confirm the role of various potential end-joining factors in DNA repair and successful female development, while in Aim 2 we perform temporally-controlled rescue experiments to determine the most critical times during development for end-joining factors. Finally in Aim 3 we will assess the impact of loss of end-joining factors on various forms of homology-dependent repair. The knowledge gained from these experiments will further inform the development of gene drive strategies for vector control as well as provide insight into processes critical for mosquito development and evolution.

Public Health Relevance

Aedes aegypti is the main vector of dengue, Zika, yellow fever and chikungunya viruses, and is a model system for studies of other mosquitoes that vector arboviruses. Gene drive strategies to introduce pathogen resistance genes into wild mosquito populations represent a powerful new control strategy, but the inability to control DNA repair choice limits the utility of many gene drive approaches. Our proposal seeks to examine DNA repair factors in this disease vector and develop strategies to influence repair pathway choice to promote recombination-based repair (gene drive).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI137112-03
Application #
9836802
Study Section
Vector Biology Study Section (VB)
Program Officer
Costero-Saint Denis, Adriana
Project Start
2018-01-03
Project End
2022-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Texas A&M Agrilife Research
Department
Zoology
Type
Earth Sciences/Resources
DUNS #
847205713
City
College Station
State
TX
Country
United States
Zip Code
77845