Dengue virus is transmitted to humans by mosquitoes. Once infected, humans may get a severe febrile illness, occasionally leading to lethal hemorrhagic fever. There has been a recent trend of increased epidemic activity and geographic expansion of dengue infection and it is considered a serious emerging global health problem. There is no vaccine available for dengue virus and there is a possibility to develop new vaccines by understanding the interactions between the virus and its mosquito vector. We performed microarray experiments to identify mosquito genes with altered expression during dengue virus infection. The data showed that infected mosquitoes have suppressed expression of many genes with diverse functions. Nine highly down-regulated genes were selected for further study. Interestingly, the overexpression of one of these genes, a member of the ubiquitin family that I named Ub3881, significantly inhibited dengue infection of mosquito cells and live mosquitoes. Other ubiquitin genes were not virally down-regulated in the microarray study and did not reduce dengue infection when overexpressed. This suggests that Ub3881 specifically inhibits dengue infection in mosquitoes. The goal of this proposal is to define the role that the Ub3881 ubiquitin family member plays in dengue infection of the mosquito vector. One function of ubiquitin proteins is to attach to proteins and label them for destruction. Another function of ubiquitin in insects is to regulate innate immune signaling through the IMD (immune deficiency) pathway. Here, we will determine whether Ub3881 binds to dengue virus proteins, labeling them for destruction and thereby altering their levels in the cell. We will also examine the effects of knocking out Ub3881 on IMD signaling during dengue infection. We expect to determine how Ub3881 inhibits dengue infection and highlight a new protein that can be used to treat and/or prevent dengue virus infection. The Fikrig laboratory at Yale University has been a wonderful environment for me to conduct research and to mature into an independent scientist. While here, I have published four articles in peer-reviewed journals and been an author on three other publications through both internal and external collaboration. I have had the chance to mentor both undergraduate and graduate students and to present my findings both at Yale and at virus conferences nationwide. Working on a day-to-day basis with highly skilled, enthusiastic researchers has been invaluable to my growth as a scientist. With this award, I will be able to move on to the next step in my career and begin independent research in a respected academic environment.

Public Health Relevance

Dengue virus is a mosquito-borne flavivirus that can infect humans and cause a severe febrile illness, occasionally leading to lethal hemorrhagic fever. There has been a recent trend of increased epidemic activity and geographic expansion of dengue infection and it is considered a serious emerging global health problem. There is no vaccine or specific antiiviral treatment available for dengue viral infection and the development of new treatments, preventative measures and vaccines may be achieved through an understanding of the interactions of dengue virus proteins with human host factors.

Agency
National Institute of Health (NIH)
Type
Career Transition Award (K22)
Project #
5K22AI103067-02
Application #
8719925
Study Section
Microbiology and Infectious Diseases Research Committee (MID)
Program Officer
Costero-Saint Denis, Adriana
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Tulane University
Department
Internal Medicine/Medicine
Type
Schools of Public Health
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118