The innate immune system is the mosquito's main line of defense against the malaria parasite Plasmodium at multiple stages of the parasite's life cycle. These immune responses are largely regulated by the TOLL and IMD pathways, which control the nuclear translocation of the NF-kappaB-like transcription factors, Rel1 and Rel2, respectively. While both pathways are implicated in anti-Plasmodium defense, we have shown that the IMD pathway is a conserved key player in regulating resistance of several Anopheles species to multiple malaria parasite species including the human pathogen P. falciparum. We have shown that the Rel2 transcription factor - mediate anti- Plasmodium action through multiple effectors and that the fitness cost of a transient induction of the Rel2 activation is minimal. As such, the IMD pathway is particularly interesting for the development of genetically modified Plasmodium resistant mosquitoes. This proposal will focus on a better understanding of the Rel2 mediated resistance to Plasmodium and thereby assess the feasibility to use this system for the development of malaria control strategies. The overall aim of this project is to develop transgenic mosquitoes that can activate Rel2 mediated anti-Plasmodium defense at an appropriate stage of infection. These mosquitoes will be used to study the regulation of this defense system and dissect the genes and mechanisms that is responsible for Plasmodium killing.

Public Health Relevance

The Anopheles mosquito uses its innate immune system to fight against a broad spectrum of microbial pathogens including the Plasmodium parasite. We have shown that the IMD immune signaling pathway is a major player in anti-Plasmodium defense. This research proposal aims at the molecular dissection of IMD pathway mediated Plasmodium resistance in A. gambiae.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI061576-10
Application #
8648967
Study Section
Vector Biology Study Section (VB)
Program Officer
Costero-Saint Denis, Adriana
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Angleró-Rodríguez, Yesseinia I; Blumberg, Benjamin J; Dong, Yuemei et al. (2016) A natural Anopheles-associated Penicillium chrysogenum enhances mosquito susceptibility to Plasmodium infection. Sci Rep 6:34084
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Dennison, Nathan J; BenMarzouk-Hidalgo, Omar J; Dimopoulos, George (2015) MicroRNA-regulation of Anopheles gambiae immunity to Plasmodium falciparum infection and midgut microbiota. Dev Comp Immunol 49:170-8
Simões, Maria L; Dimopoulos, George (2015) A mosquito mediator of parasite-induced immune priming. Trends Parasitol 31:402-4
Bahia, Ana C; Dong, Yuemei; Blumberg, Benjamin J et al. (2014) Exploring Anopheles gut bacteria for Plasmodium blocking activity. Environ Microbiol 16:2980-94
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
Pike, Andrew; Vadlamani, Alekhya; Sandiford, Simone L et al. (2014) Characterization of the Rel2-regulated transcriptome and proteome of Anopheles stephensi identifies new anti-Plasmodium factors. Insect Biochem Mol Biol 52:82-93
Dennison, Nathan J; Jupatanakul, Natapong; Dimopoulos, George (2014) The mosquito microbiota influences vector competence for human pathogens. Curr Opin Insect Sci 3:6-13

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