Since its inception, this project has comprised the first systematic examination of mechanisms of mosquito immunity and resistance to human malaria parasites in nature. Understanding the biology of these interactions could permit development of novel strategies to inhibit parasite transmission. In the current project period, we carried out a field-based genetic survey of the major human malaria vector, Anopheles gambiae, in Mali, West Africa. This work for the first time identified a significant cluster of genetic loci in A. gambiae that reduce the natural transmission of P. falciparum. This cluster, named the Plasmodium- resistance island (PRI) of A. gambiae, comprises the major genomic control region for regulation of P. falciparum infection in the A. gambiae population. Plasmodium resistance alleles in the PRI are found at high frequency in the natural vector population. We identified and characterized a candidate gene in the PRI region, called APL1, which protects mosquitoes against infection by the rodent malaria parasite, P. berghei. Here, we present new integrated Aims that build directly upon the previous work to extract the PRI trait from nature into the laboratory, and study the functional mechanisms of malaria parasite resistance controlled by alleles of the PRI. We will: 1) Functionally determine Plasmodium species-specificity of mosquito resistance mechanisms against malaria parasites using an unbiased genome-wide scanning survey. 2) Select pure lines of Plasmodium-resistant and susceptible variants from the natural P. falciparum resistance island (PRI). 3) Functionally dissect the underlying causative genomic, cellular and physiological mechanism(s) of natural Plasmodium resistance controlled by the PRI. The proposed renewal project will be the first functional study of mechanisms identified directly in a mosquito field population that confer resistance to human malaria parasites. We will comprehensively determine the validity of the robust P. berghei as a laboratory model for P. falciparum infection of mosquitoes, we will create pure resistant and susceptible mosquito lines for the natural PRI trait, and we will functionally compare the fate of parasites in the two lines and determine the mechanism of their elimination in the resistant mosquitoes, using the appropriate parasite model as determined in Aim 1.Relevance. It may be possible to develop new strategies for malaria control focusing on the mosquito vector. Knowledge of the genetic mechanisms that affect transmission of malaria by vector mosquitoes would aid in the development of such vector-based control strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042361-14
Application #
8212601
Study Section
Vector Biology Study Section (VB)
Program Officer
Costero, Adriana
Project Start
1998-08-05
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
14
Fiscal Year
2012
Total Cost
$280,710
Indirect Cost
$20,793
Name
Pasteur Institute
Department
Type
DUNS #
278151154
City
Paris Cedex 15
State
Country
France
Zip Code
75724
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Redmond, Seth N; Eiglmeier, Karin; Mitri, Christian et al. (2015) Association mapping by pooled sequencing identifies TOLL 11 as a protective factor against Plasmodium falciparum in Anopheles gambiae. BMC Genomics 16:779
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Holm, Inge; Lavazec, Catherine; Garnier, Thierry et al. (2012) Diverged alleles of the Anopheles gambiae leucine-rich repeat gene APL1A display distinct protective profiles against Plasmodium falciparum. PLoS One 7:e52684
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Mitri, Christian; Vernick, Kenneth D (2012) Anopheles gambiae pathogen susceptibility: the intersection of genetics, immunity and ecology. Curr Opin Microbiol 15:285-91
Riehle, Michelle M; Guelbeogo, Wamdaogo M; Gneme, Awa et al. (2011) A cryptic subgroup of Anopheles gambiae is highly susceptible to human malaria parasites. Science 331:596-8
Mitri, Christian; Jacques, Jean-Claude; Thiery, Isabelle et al. (2009) Fine pathogen discrimination within the APL1 gene family protects Anopheles gambiae against human and rodent malaria species. PLoS Pathog 5:e1000576
Riehle, Michelle M; Xu, Jiannong; Lazzaro, Brian P et al. (2008) Anopheles gambiae APL1 is a family of variable LRR proteins required for Rel1-mediated protection from the malaria parasite, Plasmodium berghei. PLoS One 3:e3672

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