The kdr-bearing haplotype and susceptibility to Plasmodium falciparum in Anopheles gambiae: Genetic correlation and functional testing

Christian Mitri, Kyriacos Markianos, Wamdaogo M. Guelbeogo, Emmanuel Bischoff, Awa Gneme, Karin Eiglmeier, Inge Holm, N'Fale Sagnon, Kenneth D. Vernick, Michelle M. Riehle

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Abstract

Background: Members of the Anopheles gambiae species complex are primary vectors of human malaria in Africa. It is known that a large haplotype shared between An. gambiae and Anopheles coluzzii by introgression carries point mutations of the voltage-gated sodium channel gene para, including the L1014F kdr mutation associated with insensitivity to pyrethroid insecticides. Carriage of L1014F kdr is also correlated with higher susceptibility to infection with Plasmodium falciparum. However, the genetic mechanism and causative gene(s) underlying the parasite susceptibility phenotype are not known. Methods: Mosquitoes from the wild Burkina Faso population were challenged by feeding on natural P. falciparum gametocytes. Oocyst infection phenotypes were determined and were tested for association with SNP genotypes. Candidate genes in the detected locus were prioritized and RNAi-mediated gene silencing was used to functionally test for gene effects on P. falciparum susceptibility. Results: A genetic locus, Pfin6, was identified that influences infection levels of P. falciparum in mosquitoes. The locus segregates as a ~3 Mb haplotype carrying 65 predicted genes including the para gene. The haplotype carrying the kdr allele of para is linked to increased parasite infection prevalence, but many single nucleotide polymorphisms on the haplotype are also equally linked to the infection phenotype. Candidate genes in the haplotype were prioritized and functionally tested. Silencing of para did not influence P. falciparum infection, while silencing of a predicted immune gene, serine protease ClipC9, allowed development of significantly increased parasite numbers. Conclusions: Genetic variation influencing Plasmodium infection in wild Anopheles is linked to a natural ~3 megabase haplotype on chromosome 2L that carries the kdr allele of the para gene. Evidence suggests that para gene function does not directly influence parasite susceptibility, and the association of kdr with infection may be due to tight linkage of kdr with other gene(s) on the haplotype. Further work will be required to determine if ClipC9 influences the outcome of P. falciparum infection in nature, as well as to confirm the absence of a direct influence by para.

Original languageEnglish (US)
Article number391
JournalMalaria Journal
Volume14
Issue number1
DOIs
StatePublished - Oct 6 2015

Bibliographical note

Funding Information:
We thank Xuanzhong Li for assistance with bioinformatic analysis. We thank the CEPIA platform of the Institut Pasteur and Emma Brito-Fravallo for rearing and infecting mosquitoes. This work received financial support to KDV from the European Commission, FP7 Infrastructures #228421 Infravec; European Research Council, Support for frontier research, Advanced Grant #323173; National Institutes of Health, NIAID R01 #AI073685; and French Laboratoire d’Excellence “Integrative Biology of Emerging Infectious Diseases”#ANR-10-LABX-62-IBEID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Chip hybridization was performed at the BCH IDDRC Molecular Genetics Core Facility at Children’s Hospital Boston supported by NIH-P30-HD18655.

Publisher Copyright:
© 2015 Mitri et al.

Keywords

  • Haplotype
  • Host-pathogen interaction
  • Malaria
  • Mosquito

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