Natural malaria infection in Anopheles gambiae is regulated by a single genomic control region. Science

Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States
Science (Impact Factor: 33.61). 05/2006; 312(5773):577-9. DOI: 10.1126/science.1124153
Source: PubMed


We surveyed an Anopheles gambiae population in a West African malaria transmission zone for naturally occurring genetic loci that control mosquito infection
with the human malaria parasite, Plasmodium falciparum. The strongest Plasmodium resistance loci cluster in a small region of chromosome 2L and each locus explains at least 89% of parasite-free mosquitoes
in independent pedigrees. Together, the clustered loci form a genomic Plasmodium-resistance island that explains most of the genetic variation for malaria parasite infection of mosquitoes in nature. Among
the candidate genes in this chromosome region, RNA interference knockdown assays confirm a role in Plasmodium resistance for Anopheles Plasmodium-responsive leucine-rich repeat 1 (APL1), encoding a leucine-rich repeat protein that is similar to molecules involved in natural pathogen resistance mechanisms
in plants and mammals.

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Available from: Sory Diawara
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    • "Several studies have been performed by distinct research groups allowing the characteristics of P. falciparum inside some important vectors from Africa and Asia, including the molecular aspects of the interaction and the immune response to the parasite infection to be understood (Rodrigues et al. 2012, Ramirez et al. 2014). Additionally, studies have shown that mosquito species exhibit a wide range of susceptibility to infection with a given P. falciparum line (Collins et al. 1986, Lambrechts et al. 2005) and different Plasmodium isolates also vary in their ability to infect a given mosquito strain (Niare et al. 2002, Lambrechts et al. 2005, Riehle et al. 2006). A degree of adaptation was suggested between geographically isolated populations of An. gambiae and P. falciparum when an An. "
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    ABSTRACT: In the Americas, areas with a high risk of malaria transmission are mainly located in the Amazon Forest, which extends across nine countries. One keystone step to understanding the Plasmodium life cycle in Anopheles species from the Amazon Region is to obtain experimentally infected mosquito vectors. Several attempts to colonise Ano- pheles species have been conducted, but with only short-lived success or no success at all. In this review, we review the literature on malaria transmission from the perspective of its Amazon vectors. Currently, it is possible to develop experimental Plasmodium vivax infection of the colonised and field-captured vectors in laboratories located close to Amazonian endemic areas. We are also reviewing studies related to the immune response to P. vivax infection of Anopheles aquasalis, a coastal mosquito species. Finally, we discuss the importance of the modulation of Plasmodium infection by the vector microbiota and also consider the anopheline genomes. The establishment of experimental mosquito infections with Plasmodium falciparum, Plasmodium yoelii and Plasmodium berghei parasites that could provide interesting models for studying malaria in the Amazonian scenario is important. Understanding the molecular mechanisms involved in the development of the parasites in New World vectors is crucial in order to better determine the interaction process and vectorial competence.
    Full-text · Article · Feb 2015 · Memórias do Instituto Oswaldo Cruz
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    • "Naturally occurring SNPs within A. gambiae immune genes have been found to be associated with parasite infection, including TOLL5B and ILP3[49] as well as Sp SNAKElike and TOLL6[50]. Indeed, it has been proposed that a breakdown in mosquito innate immunity is responsible for susceptibility to parasite infection [51], raising the possibility of undertaking studies searching for naturally occurring mutations in immune signaling genes. Most recently, Li et al.[52] identified nonsynonymous SNPs in A. gambiae adenosine deaminase (AgADA), fibrinogen-related protein 1 (FREP1) and fibrinogen-related protein 30 (FBN30). "
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    ABSTRACT: Background Susceptibility to Plasmodium infection in Anopheles gambiae has been proposed to result from naturally occurring polymorphisms that alter the strength of endogenous innate defenses. Despite the fact that some of these mutations are known to introduce non-synonymous substitutions in coding sequences, these mutations have largely been used to rationalize knockdown of associated target proteins to query the effects on parasite development in the mosquito host. Here, we assay the effects of engineered mutations on an immune signaling protein target that is known to control parasite sporogonic development. By this proof-of-principle work, we have established that naturally occurring mutations can be queried for their effects on mosquito protein function and on parasite development and that this important signaling pathway can be genetically manipulated to enhance mosquito resistance. Methods We introduced SNPs into the A. gambiae MAPK kinase MEK to alter key residues in the N-terminal docking site (D-site), thus interfering with its ability to interact with the downstream kinase target ERK. ERK phosphorylation levels in vitro and in vivo were evaluated to confirm the effects of MEK D-site mutations. In addition, overexpression of various MEK D-site alleles was used to assess P. berghei infection in A. gambiae. Results The MEK D-site contains conserved lysine residues predicted to mediate protein-protein interaction with ERK. As anticipated, each of the D-site mutations (K3M, K6M) suppressed ERK phosphorylation and this inhibition was significant when both mutations were present. Tissue-targeted overexpression of alleles encoding MEK D-site polymorphisms resulted in reduced ERK phosphorylation in the midgut of A. gambiae. Furthermore, as expected, inhibition of MEK-ERK signaling due to D-site mutations resulted in reduction in P. berghei development relative to infection in the presence of overexpressed catalytically active MEK. Conclusion MEK-ERK signaling in A. gambiae, as in model organisms and humans, depends on the integrity of conserved key residues within the MEK D-site. Disruption of signal transmission via engineered SNPs provides a purposeful proof-of-principle model for the study of naturally occurring mutations that may be associated with mosquito resistance to parasite infection as well as an alternative genetic basis for manipulation of this important immune signaling pathway.
    Full-text · Article · Jun 2014 · Parasites & Vectors
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    • "gambiae (Petrarca and Beier, 1992; Costantini et al., 1999). A cluster of resistance genes has been located within inversion 2La in An. gambiae (Riehle et al., 2006). Although still controversial, several studies have revealed Plasmodium infection to incur a fitness cost to Anopheles, mainly in reduced fecundity and/or survival (Hurd et al., 2005). "
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    ABSTRACT: Chromosomal inversions have been repeatedly involved in local adaptation in a large number of animals and plants. The ecological and behavioral plasticity of Anopheles species-human malaria vectors-is mirrored by high amounts of polymorphic inversions. The adaptive significance of chromosomal inversions has been consistently attested by strong and significant correlations between their frequencies and a number of phenotypic traits. Here, we provide an extensive literature review of the different adaptive traits associated with chromosomal inversions in the genus Anopheles. Traits having important consequences for the success of present and future vector control measures, such as insecticide resistance and behavioral changes, are discussed.
    Full-text · Article · May 2014 · Frontiers in Genetics
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