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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Vector Biology Study Section (VB)
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Costero, Adriana
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Johns Hopkins University
Schools of Public Health
United States
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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
Clayton, April M; Dong, Yuemei; Dimopoulos, George (2014) The Anopheles innate immune system in the defense against malaria infection. J Innate Immun 6:169-81
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Sanders, Natalie G; Sullivan, David J; Mlambo, Godfree et al. (2014) Gametocytocidal screen identifies novel chemical classes with Plasmodium falciparum transmission blocking activity. PLoS One 9:e105817
Blumberg, Benjamin J; Trop, Stefanie; Das, Suchismita et al. (2013) Bacteria- and IMD pathway-independent immune defenses against Plasmodium falciparum in Anopheles gambiae. PLoS One 8:e72130
Clayton, April M; Cirimotich, Chris M; Dong, Yuemei et al. (2013) Caudal is a negative regulator of the Anopheles IMD pathway that controls resistance to Plasmodium falciparum infection. Dev Comp Immunol 39:323-32
Bian, Guowu; Joshi, Deepak; Dong, Yuemei et al. (2013) Wolbachia invades Anopheles stephensi populations and induces refractoriness to Plasmodium infection. Science 340:748-51
Sim, Shuzhen; Ramirez, Jose 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
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