Dengue virus is one of the most important arboviral pathogens, with at least 2.5 million people at risk of contracting dengue fever and dengue hemorrhagic fever. We have already made a leap in the past year towards the understanding on how the mosquito's innate immune system is involved in limiting dengue infection. The research plan outlined in this proposal will take this study further and contribute to a better understanding of the mosquito innate immune defenses against dengue virus infection and it would provide the basis for novel anti-viral strategies. To accomplish these goals, two aims are set forward:
The first aim i s to characterize the molecular immune responses of the mosquito Aedes aegypti. Specifically, the proposed experimental assays will provide insightful information on the relative importance of each mosquito tissue in the response to dengue virus infection, and it will contribute towards the elucidation of the molecular mechanisms that underlie an immune response-dependent infection barrier. Transcriptional dissection of tissue and stage specific immune responses will be elucidated through whole genome microarray assays and hierarchical clustering analysis. The inclusion of Ae. aegypti susceptible and refractory strains and its corresponding analyses of immune responses to varying dengue serotypes is expected to provide insights into the immune mechanisms that define resistance to infection.
The second aim constitutes a functional screening of candidate anti-dengue effector genes. These candidates will be selected by merging the expression data analyses conducted in Aim 1, literature studies, and homology searches. RNAi gene silencing assays will then be conducted to functionally confirm the potential anti-dengue effect of selected genes. The anti-viral effector molecules identified in this research are expected to contribute to the development of novel dengue control strategies. From the stand of public health, the knowledge gathered from this research will greatly contribute to our understanding of dengue transmission and other important arboviral pathogens of great public health significance, such as the West Nile virus and the yellow fever virus. This, in turn, will allow us to better direct or design novel anti-dengue control strategies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-DIG-E (29))
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Adger-Johnson, Diane S
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Johns Hopkins University
Schools of Public Health
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Ramirez, Jose Luis; Short, Sarah M; Bahia, Ana C et al. (2014) Chromobacterium Csp_P reduces malaria and dengue infection in vector mosquitoes and has entomopathogenic and in vitro anti-pathogen activities. PLoS Pathog 10:e1004398
Sim, Shuzhen; Jupatanakul, Natapong; Ramirez, José L et al. (2013) Transcriptomic profiling of diverse Aedes aegypti strains reveals increased basal-level immune activation in dengue virus-refractory populations and identifies novel virus-vector molecular interactions. PLoS Negl Trop Dis 7:e2295
Ramirez, Jose Luis; Souza-Neto, Jayme; Torres Cosme, Rolando et al. (2012) Reciprocal tripartite interactions between the Aedes aegypti midgut microbiota, innate immune system and dengue virus influences vector competence. PLoS Negl Trop Dis 6:e1561
Sim, Shuzhen; Ramirez, José L; Dimopoulos, George (2012) Dengue virus infection of the Aedes aegypti salivary gland and chemosensory apparatus induces genes that modulate infection and blood-feeding behavior. PLoS Pathog 8:e1002631
Dong, Yuemei; Morton Jr, James C; Ramirez, Jose Luis et al. (2012) The entomopathogenic fungus Beauveria bassiana activate toll and JAK-STAT pathway-controlled effector genes and anti-dengue activity in Aedes aegypti. Insect Biochem Mol Biol 42:126-32
Cirimotich, Chris M; Ramirez, Jose L; Dimopoulos, George (2011) Native microbiota shape insect vector competence for human pathogens. Cell Host Microbe 10:307-10
Ramirez, Jose L; Dimopoulos, George (2010) The Toll immune signaling pathway control conserved anti-dengue defenses across diverse Ae. aegypti strains and against multiple dengue virus serotypes. Dev Comp Immunol 34:625-9
Bartholomay, Lyric C; Waterhouse, Robert M; Mayhew, George F et al. (2010) Pathogenomics of Culex quinquefasciatus and meta-analysis of infection responses to diverse pathogens. Science 330:88-90
Ramirez, José L; Garver, Lindsey S; Dimopoulos, George (2009) Challenges and approaches for mosquito targeted malaria control. Curr Mol Med 9:116-30