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)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI061576-08
Application #
8238194
Study Section
Vector Biology Study Section (VB)
Program Officer
Costero, Adriana
Project Start
2004-07-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
8
Fiscal Year
2012
Total Cost
$405,900
Indirect Cost
$158,400
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kefi, Mary; Mavridis, Konstantinos; Simões, Maria L et al. (2018) New rapid one-step PCR diagnostic assay for Plasmodium falciparum infective mosquitoes. Sci Rep 8:1462
Pike, Andrew; Dong, Yuemei; Dizaji, Nahid Borhani et al. (2017) Changes in the microbiota cause genetically modified Anopheles to spread in a population. Science 357:1396-1399
de Mendonça Amarante, Anderson; Jupatanakul, Natapong; de Abreu da Silva, Isabel Caetano et al. (2017) The DNA chaperone HMGB1 potentiates the transcriptional activity of Rel1A in the mosquito Aedes aegypti. Insect Biochem Mol Biol 80:32-41
Simões, Maria L; Dong, Yuemei; Hammond, Andrew et al. (2017) The Anopheles FBN9 immune factor mediates Plasmodium species-specific defense through transgenic fat body expression. Dev Comp Immunol 67:257-265
Simões, Maria L; Mlambo, Godfree; Tripathi, Abhai et al. (2017) Immune Regulation of Plasmodium Is Anopheles Species Specific and Infection Intensity Dependent. MBio 8:
Saraiva, Raúl G; Kang, Seokyoung; Simões, Maria L et al. (2016) Mosquito gut antiparasitic and antiviral immunity. Dev Comp Immunol 64:53-64
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
Barletta, Ana Beatriz Ferreira; Alves, Liliane Rosa; Silva, Maria Clara L Nascimento et al. (2016) Emerging role of lipid droplets in Aedes aegypti immune response against bacteria and Dengue virus. Sci Rep 6:19928
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