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  • Good morning, I’m Stephanie Blandin and I work in Strasbourg (far east of France). In the lab, we study the immune responses of the malaria mosquito A. gambiae. These mosq are major vectors of P. parasites, causing malaria in 250 millions people each year, and leading to 0.8 million deaths, mostly … In my presentation, we will also look at host / pathogen interactions, however not in humans, but in the insect.
  • - Within the A. gambiae species, the ability to transmit malaria parasites varies extensively btw indiv, with some mosq fully resistant to the parasite and therefore unable to transmit the disease Our goal: understand what makes these mosq resistant and potentially exploit this naturally occurring resistance to control malaria transmission in the field Indeed, the transmission cycle can be interrupted at any stage. Most antimalarial strategies currently on the market or in development target parasite in the human host using drugs or vaccines, attempt to decrease vector populations using insecticides, or limit the number of mosquito bites per person using insecticide treated bednets. In our case, we would like to understand how resistant mosquitoes eliminate malaria parasites, to provide a new handle towards malaria eradication
  • Female mosq unptake parasites while feeding on an infected host. For this mosq to become infective, the parasite must complete a complex devt cycle within the mosq, from the midgut where it begins its journey, to the salivary glands where parasites are injected to the next host During its dev in the mosq Parasite undergoes massive losses, especially early after infection, suggesting mosq are able to limit parasite dev This antiparasitic response is extreme in resistant mosquitoes: all parasites are killed when they traverse the midgut, and consequently, resistant mosquitoes do not transmit the disease. Possible to genetically isolate mosq strains that are resistant, demonstrating genetic factors This is a typical midgut from a susc mosq infected with a rodent malaria parasite expressing GFP that we use as a model of infection in the lab. In contrast, res mosq are devoid of live parasites
  • To ID the genetic factors that control resistance, we first mapped the genomic regions where they are located in a cross between susceptible and resistant mosquitoes Resistance was linked to a major resistance locus on Chrom 3, containing 1000 genes A major challenge is to identify the causative genes and polymorphisms that account for the trait within this locus. Still, we were lucky in our case, as we had a very good candidate gene in the center of this interval: the thioester-containing protein TEP1
  • Indeed we had previously reported that TEP1 labels Plasmodium parasites and triggers their killing. The depletion of TEP1 in resistant mosquitoes renders them susceptible to the parasite. Belongs to family of CF and A2Ms. Despite low homology at seq level, crystal structure very close to that of CF3 Like CF, it circulates in Hm. Recently showed that it forms a complex with 2 LRR proteins – not reported in mammalian complement system It binds to bact surface and promotes phagocytosis – reminiscent of CF function Polymorphic in susceptible and resistant mosq lines => This led us to ask whether the different alleles of TEP1 have different efficiencies in parasite killing
  • To address this question, we set up a new assay called reciprocal allele-specific RNAi that allowed us to compare the 2 alleles in the same genetic background… The different groups of mosq were infected with rodent parasite Pb. Each dot represent number of parasites developing in a single mosq Mosq expressing only the allele from the susceptible strain were more susceptible than those expressing only the allele from the resistant strain, demonstrating that polymorphisms at the TEP1 locus confer resistance to malaria parasites And identifying the first resistance genetic factor in mosquitoes. Still, picture is not complete and we showed that other loci must contribute to fully account for the resistance trait
  • We aim at identifying these additional factors, and understanding how they interact to control resistance to rodent and human malaria parasites in the lab and in field mosquitoes Of note, the outcome of an infection is not only determined by the mosquito genotype, parasite virulence and environmental factors are also important. Together with other groups, we also investigate the complexity of the interactions between these factors in the field. This work is based on an extensive collaboration with laboratories in Africa with access to experimental field infections Foreseen applications of this work could be the design of new strategies to control malaria transmission, or the improvement of existing ones, for instance by developing diagnostic tools to survey resistance to malaria parasites in field mosquitoes, and targeting insecticides to mosquito populations that are susceptible to parasites.

1.7 stephanie blandin 1.7 stephanie blandin Presentation Transcript

  • Stephanie Blandin – IBMC Strasbourg – INSERM U963 Mosquito resistance to malaria parasites: Genetic intelligence against disease transmission
  • Malaria transmission cycle malaria 250.000.000 cases / year 860.000 deaths / year Anopheles gambiae CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD Plasmodium
  • Anopheles gambiae Some mosquitoes are resistant to malaria parasites…
    • Why?
    • Potential applications
    CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD Plasmodium
  • Mosquito genetic factors control susceptibility Midgut Salivary Glands Resistant Susceptible Laboratory model: A. gambiae / Plasmodium berghei Midguts infected with GFP parasites
  • Resistance to parasites is linked to a major locus Candidate gene within locus: TEP1 (ThioEster containing Protein 1) Resistance Clearance Quantitative Traits: Blandin, Science 2009 1000 genes
  • TEP1 has antiparasitic activity
    • Labels bacteria for phagocytosis
    • Labels malaria parasites and promotes their killing
    • Circulates in hemolymph as a complex with LRR proteins
    • Polymorphic
    • Complement-like protein
    Control TEP1-depleted Resistant mosquitoes, 8 days post infection Blandin, Cell 2004
  • TEP1 polymorphisms confer resistance to parasites Reciprocal allele-specific RNA interference Blandin, Science 2009 RxS cross infected with P. berghei
  • Perspectives in mosquito control for global malaria eradication
    • Understand resistance:
      • Mosquito genetics
      • Parasite virulence
      • Environment
    • Collaborators in Africa
      • IRD-OCEAC Cameroon
      • ICIPE Kenya
      • MRTC Mali
    Laboratory
    • Diagnostics of mosquito resistance to parasites
    • Kill malaria susceptible mosquitoes, not resistant ones
    Applications