The kdr-bearing haplotype and susceptibility to Plasmodium falciparum in Anopheles gambiae: genetic correlation and functional testing
Tóm tắt
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. 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. 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. 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.
Tài liệu tham khảo
Githeko AK, Service MW, Mbogo CM, Atieli FK. Resting behaviour, ecology and genetics of malaria vectors in large scale agricultural areas of Western Kenya. Parassitologia. 1996;38:481–9.
Martinez-Torres D, Chandre F, Williamson MS, Darriet F, Berge JB, Devonshire AL, et al. Molecular characterization of pyrethroid knockdown resistance (kdr) in the major malaria vector Anopheles gambiae s.s. Insect Mol Biol. 1998;7:179–84.
Riehle MM, Markianos K, Niare O, Xu J, Li J, Toure AM, et al. Natural malaria infection in Anopheles gambiae is regulated by a single genomic control region. Science. 2006;312:577–9.
Takken W, Verhulst NO. Host preferences of blood-feeding mosquitoes. Annu Rev Entomol. 2013;58:433–53.
Menge DM, Zhong D, Guda T, Gouagna LC, Githure JI, Beier J, et al. Quantitative trait loci controlling refractoriness to Plasmodium falciparum in natural Anopheles gambiae from a malaria endemic region in Western Kenya. Genetics. 2006;173:1337–45.
Riehle MM, Markianos K, Lambrechts L, Xia A, Sharakhov I, Koella JC, et al. A major genetic locus controlling natural Plasmodium falciparum infection is shared by East and West African Anopheles gambiae. Malar J. 2007;6:87.
Collins FH, Sakai RK, Vernick KD, Paskewitz S, Seeley DC, Miller LH, et al. Genetic selection of a Plasmodium-refractory strain of the malaria vector Anopheles gambiae. Science. 1986;234:607–10.
Harris C, Lambrechts L, Rousset F, Abate L, Nsango SE, Fontenille D, et al. Polymorphisms in Anopheles gambiae immune genes associated with natural resistance to Plasmodium falciparum. PLoS Pathog. 2010;6:e1001112.
Horton AA, Lee Y, Coulibaly CA, Rashbrook VK, Cornel AJ, Lanzaro GC, et al. Identification of three single nucleotide polymorphisms in Anopheles gambiae immune signaling genes that are associated with natural Plasmodium falciparum infection. Malar J. 2010;9:160.
Ffrench-Constant RH. The molecular genetics of insecticide resistance. Genetics. 2013;194:807–15.
Miyazaki M, Ohyama K, Dunlap DY, Matsumura F. Cloning and sequencing of the para-type sodium channel gene from susceptible and kdr-resistant German cockroaches (Blattella germanica) and house fly (Musca domestica). Mol Gen Genet. 1996;252:61–8.
Williamson MS, Martinez-Torres D, Hick CA, Devonshire AL. Identification of mutations in the housefly para-type sodium channel gene associated with knockdown resistance (kdr) to pyrethroid insecticides. Mol Gen Genet. 1996;252:51–60.
Jones CM, Liyanapathirana M, Agossa FR, Weetman D, Ranson H, Donnelly MJ, et al. Footprints of positive selection associated with a mutation (N1575Y) in the voltage-gated sodium channel of Anopheles gambiae. Proc Natl Acad Sci USA. 2012;109:6614–9.
Pinto J, Lynd A, Vicente JL, Santolamazza F, Randle NP, Gentile G, et al. Multiple origins of knockdown resistance mutations in the Afrotropical mosquito vector Anopheles gambiae. PLoS One. 2007;2:e1243.
Ranson H, Jensen B, Vulule JM, Wang X, Hemingway J, Collins FH. Identification of a point mutation in the voltage-gated sodium channel gene of Kenyan Anopheles gambiae associated with resistance to DDT and pyrethroids. Insect Mol Biol. 2000;9:491–7.
Kabula B, Kisinza W, Tungu P, Ndege C, Batengana B, Kollo D, et al. Co-occurrence and distribution of East (L1014S) and West (L1014F) African knock-down resistance in Anopheles gambiae sensu lato population of Tanzania. Trop Med Int Health. 2014;19:331–41.
Namountougou M, Diabate A, Etang J, Bass C, Sawadogo SP, Gnankinie O, et al. First report of the L1014S kdr mutation in wild populations of Anopheles gambiae M and S molecular forms in Burkina Faso (West Africa). Acta Trop. 2013;125:123–7.
Djegbe I, Agossa FR, Jones CM, Poupardin R, Cornelie S, Akogbeto M, et al. Molecular characterization of DDT resistance in Anopheles gambiae from Benin. Parasit Vectors. 2014;7:409.
Coetzee M, Hunt RH, Wilkerson R, Della Torre A, Coulibaly MB, Besansky NJ. Anopheles coluzzii and Anopheles amharicus, new members of the Anopheles gambiae complex. Zootaxa. 2013;3619:246–74.
Santolamazza F, Calzetta M, Etang J, Barrese E, Dia I, Caccone A, et al. Distribution of knock-down resistance mutations in Anopheles gambiae molecular forms in west and west-central Africa. Malar J. 2008;7:74.
Diabate A, Brengues C, Baldet T, Dabire KR, Hougard JM, Akogbeto M, et al. The spread of the Leu-Phe kdr mutation through Anopheles gambiae complex in Burkina Faso: genetic introgression and de novo phenomena. Trop Med Int Health. 2004;9:1267–73.
Weill M, Chandre F, Brengues C, Manguin S, Akogbeto M, Pasteur N, et al. The kdr mutation occurs in the Mopti form of Anopheles gambiae s.s. through introgression. Insect Mol Biol. 2000;9:451–5.
Norris LC, Main BJ, Lee Y, Collier TC, Fofana A, Cornel AJ, et al. Adaptive introgression in an African malaria mosquito coincident with the increased usage of insecticide-treated bed nets. Proc Natl Acad Sci USA. 2015;112:815–20.
Clarkson CS, Weetman D, Essandoh J, Yawson AE, Maslen G, Manske M, et al. Adaptive introgression between Anopheles sibling species eliminates a major genomic island but not reproductive isolation. Nat Commun. 2014;5:4248.
Lynd A, Weetman D, Barbosa S, Egyir Yawson A, Mitchell S, Pinto J, et al. Field, genetic, and modeling approaches show strong positive selection acting upon an insecticide resistance mutation in Anopheles gambiae s.s. Mol Biol Evol. 2010;27:1117–25.
Ndiath MO, Cailleau A, Diedhiou SM, Gaye A, Boudin C, Richard V, et al. Effects of the kdr resistance mutation on the susceptibility of wild Anopheles gambiae populations to Plasmodium falciparum: a hindrance for vector control. Malar J. 2014;13:340.
Alout H, Ndam NT, Sandeu MM, Djegbe I, Chandre F, Dabire RK, et al. Insecticide resistance alleles affect vector competence of Anopheles gambiae s.s. for Plasmodium falciparum field isolates. PLoS One. 2013;8:e63849.
Riehle MM, Guelbeogo WM, Gneme A, Eiglmeier K, Holm I, Bischoff E, et al. A cryptic subgroup of Anopheles gambiae is highly susceptible to human malaria parasites. Science. 2011;331:596–8.
Gneme A, Guelbeogo WM, Riehle MM, Sanou A, Traore A, Zongo S, et al. Equivalent susceptibility of Anopheles gambiae M and S molecular forms and Anopheles arabiensis to Plasmodium falciparum infection in Burkina Faso. Malar J. 2013;12:204.
Fanello C, Santolamazza F, della Torre A. Simultaneous identification of species and molecular forms of the Anopheles gambiae complex by PCR-RFLP. Med Vet Entomol. 2002;16:461–4.
Niare O, Markianos K, Volz J, Oduol F, Toure A, Bagayoko M, et al. Genetic loci affecting resistance to human malaria parasites in a West African mosquito vector population. Science. 2002;298:213–6.
Singer VL, Jones LJ, Yue ST, Haugland RP. Characterization of PicoGreen reagent and development of a fluorescence-based solution assay for double-stranded DNA quantitation. Anal Biochem. 1997;249:228–38.
GenomeStudio Genotyping Module User Guide (PDF document), http://support.illumina.com/content/dam/illumina-support/documents/myillumina/d2c2c169-36c7-4613-89d6-bf34588a7624/genomestudio_gt_module_v1.0_ug_11319113_reva.pdf [http://support.illumina.com/content/dam/illumina-support/documents/myillumina/d2c2c169-36c7-4613-89d6-bf34588a7624/genomestudio_gt_module_v1.0_ug_11319113_reva.pdf].
Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.
Mitri C, Jacques JC, Thiery I, Riehle MM, Xu J, Bischoff E, et al. Fine pathogen discrimination within the APL1 gene family protects Anopheles gambiae against human and rodent malaria species. PLoS Pathog. 2009;5:e1000576.
Fisher RA. Statistical methods for research workers. Edinburgh: Oliver & Boyd; 1954.
Crawford JE, Bischoff E, Garnier T, Gneme A, Eiglmeier K, Holm I, et al. Evidence for population-specific positive selection on immune genes of Anopheles gambiae. G3 (Bethesda). 2012;2:1505–19.
Lee Y, Marsden CD, Norris LC, Collier TC, Main BJ, Fofana A, et al. Spatiotemporal dynamics of gene flow and hybrid fitness between the M and S forms of the malaria mosquito, Anopheles gambiae. Proc Natl Acad Sci USA. 2013;110:19854–9.
Price AL, Zaitlen NA, Reich D, Patterson N. New approaches to population stratification in genome-wide association studies. Nat Rev Genet. 2010;11:459–63.
Ligoxygakis P, Pelte N, Hoffmann JA, Reichhart JM. Activation of Drosophila Toll during fungal infection by a blood serine protease. Science. 2002;297:114–6.
Luo H, Rose PE, Roberts TM, Dearolf CR. The Hopscotch Jak kinase requires the Raf pathway to promote blood cell activation and differentiation in Drosophila. Mol Genet Genom. 2002;267:57–63.
Baton LA, Robertson A, Warr E, Strand MR, Dimopoulos G. Genome-wide transcriptomic profiling of Anopheles gambiae hemocytes reveals pathogen-specific signatures upon bacterial challenge and Plasmodium berghei infection. BMC Genom. 2009;10:257.
Dong Y, Aguilar R, Xi Z, Warr E, Mongin E, Dimopoulos G. Anopheles gambiae immune responses to human and rodent Plasmodium parasite species. PLoS Pathog. 2006;2:e52.
Holm I, Lavazec C, Garnier T, Mitri C, Riehle MM, Bischoff E, et al. Diverged alleles of the Anopheles gambiae leucine-rich repeat gene APL1A display distinct protective profiles against Plasmodium falciparum. PLoS One. 2012;7:e52684.
Fryxell RT, Nieman CC, Fofana A, Lee Y, Traore SF, Cornel AJ, et al. Differential Plasmodium falciparum infection of Anopheles gambiae s.s. molecular and chromosomal forms in Mali. Malar J. 2012;11:133.
Gneme A, Guelbeogo WM, Riehle MM, Tiono AB, Diarra A, Kabre GB, et al. Plasmodium species occurrence, temporal distribution and interaction in a child-aged population in rural Burkina Faso. Malar J. 2013;12:67.
Ndiath MO, Brengues C, Konate L, Sokhna C, Boudin C, Trape JF, et al. Dynamics of transmission of Plasmodium falciparum by Anopheles arabiensis and the molecular forms M and S of Anopheles gambiae in Dielmo, Senegal. Malar J. 2008;7:136.
Wondji C, Frederic S, Petrarca V, Etang J, Santolamazza F, Della Torre A, et al. Species and populations of the Anopheles gambiae complex in Cameroon with special emphasis on chromosomal and molecular forms of Anopheles gambiae s.s. J Med Entomol. 2005;42:998–1005.
Ndiath MO, Sougoufara S, Gaye A, Mazenot C, Konate L, Faye O, et al. Resistance to DDT and pyrethroids and increased kdr mutation frequency in An. gambiae after the implementation of permethrin-treated nets in Senegal. PLoS One. 2012;7:e31943.
Padonou GG, Sezonlin M, Osse R, Aizoun N, Oke-Agbo F, Oussou O, et al. Impact of 3 years of large scale Indoor Residual Spraying (IRS) and Insecticide Treated Nets (ITNs) interventions on insecticide resistance in Anopheles gambiae s.l. in Benin. Parasit Vectors. 2012;5:72.
Rottschaefer SM, Riehle MM, Coulibaly B, Sacko M, Niare O, Morlais I, et al. Exceptional diversity, maintenance of polymorphism, and recent directional selection on the APL1 malaria resistance genes of Anopheles gambiae. PLoS Biol. 2011;9:e1000600.
White BJ, Lawniczak MK, Cheng C, Coulibaly MB, Wilson MD, Sagnon N, et al. Adaptive divergence between incipient species of Anopheles gambiae increases resistance to Plasmodium. Proc Natl Acad Sci USA. 2011;108:244–9.
Gene Dmel\para. http://flybase.org/reports/FBgn0264255.html. Last accessed 20 Dec 2014. [http://flybase.org/reports/FBgn0264255.html].
Parker L, Padilla M, Du Y, Dong K, Tanouye MA. Drosophila as a model for epilepsy: bss is a gain-of-function mutation in the para sodium channel gene that leads to seizures. Genetics. 2011;187:523–34.
Stone B, Evans L, Coleman J, Kuebler D. Genetic and pharmacological manipulations that alter metabolism suppress seizure-like activity in Drosophila. Brain Res. 2013;1496:94–103.
Coulibaly D, Travassos MA, Kone AK, Tolo Y, Laurens MB, Traore K, et al. Stable malaria incidence despite scaling up control strategies in a malaria vaccine-testing site in Mali. Malar J. 2014;13:374.
Trape JF, Tall A, Diagne N, Ndiath O, Ly AB, Faye J, et al. Malaria morbidity and pyrethroid resistance after the introduction of insecticide-treated bednets and artemisinin-based combination therapies: a longitudinal study. Lancet Infect Dis. 2011;11:925–32.
Zhou G, Afrane YA, Vardo-Zalik AM, Atieli H, Zhong D, Wamae P, Himeidan YE, et al. Changing patterns of malaria epidemiology between 2002 and 2010 in Western Kenya: the fall and rise of malaria. PLoS One. 2011;6:e20318.