Arthropod-borne pathogens account for millions of death each year. Understanding the genetic basis of vector susceptibility to pathogens is pivotal to novel disease control strategies. The hypothesis that induction of apoptosis is a fundamental innate immune response has been supported by virology studies, which demonstrated that the anti- apoptotic activities of many viral genes are essential for their infectivity and/or virulence. However, the cellular mechanism mediating the induction of apoptosis following virus infection remained enigmatic. In addition, studies with cultured insect cells showed that either there is a lack of apoptosis, or the pro-apoptotic response happens relatively late, casting doubt on the functional significance of apoptosis as an innate immunity. Using in vivo mosquito models mimicking native routes of viral infection, we found that there is a rapid induction of pro-apoptotic genes (RIPAG) within a few hours following exposure to DNA/RNA viruses. More importantly, using genetic tools in Drosophila, we showed that the RIPAG, and the ensuing apoptosis, is responsible for denying the expression of viral genes and blocking/limiting the infection. Animals with compromised RIAPG are much more susceptible to viral infection than wild type. In this proposal, we seek to unravel the transcriptional mechanisms and the regulatory pathway(s) controlling RIPAG using a combination of Drosophila genetics and comparative genomics. In addition, utilizing the information obtained through the mechanistic analysis, we will test the hypothesis that increased innate immunity against viral infection may be achieved by enhancing the RIPAG response to viral infection. Finally, we assess the fitness of the antiviral constructs we create in Drosophila, then translate the most powerful and most fit constructs to two mosquito vectors and perform preliminary evaluations of transgene effectiveness against Dengue.

Public Health Relevance

Arthropod-borne pathogens account for millions of death each year. Understanding the genetic basis controlling vector susceptibility to intracellular pathogens is pivotal to novel disease control strategies. The knowledge gained from this study should have significant impact for combating arthropod-born diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM106174-01A1
Application #
8631806
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Dunsmore, Sarah
Project Start
2014-02-01
Project End
2017-12-31
Budget Start
2014-02-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$284,050
Indirect Cost
$94,050
Name
University of Florida
Department
Genetics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611