Genome-based diagnostics for mapping, monitoring and management of insecticide resistance in major African malaria vectors

基于基因组的诊断，用于绘制、监测和管理非洲主要疟疾病媒的杀虫剂抗药性

• 批准号: 10631175
• 负责人: Martin James Donnelly
• 金额: $ 48.53万
• 依托单位: TMLIVERPOOL SCHOOL OF TROPICAL MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631175
• 关键词: Adoption; Africa; Africa South of the Sahara; African; Anopheles Genus; Anopheles gambiae; Award; Biological Assay; CRISPR/Cas technology; Cessation of life; Chemicals; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Country; Culicidae; Data; Development; Diagnostic; Economic Development; Epidemiology; Evaluation; Evolution; Falciparum Malaria; Future; Gene Frequency; Genetic; Genetic Markers; Genetic Models; Genetic Transformation; Genome; Genomic Segment; Genomic approach; Genomics; Goals; Heterogeneity; Insecticide Resistance; Insecticides; Intervention; Kenya; Malaria; Maps; Marker Discovery; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; Outcome; Population; Predisposition; Randomized, Controlled Trials; Recommendation; Research Project Grants; Resistance; Resistance development; Resources; Site; Speed; Surveillance Program; Technology; Testing; Treatment Efficacy; Uganda; Variant; Work; biomarker identification; biomarker panel; control trial; diagnostic biomarker; epidemiologic data; functional genomics; genetic resistance; genetic variant; genome sequencing; genome wide association study; genomic signature; improved; malaria infection; malaria transmission; mortality; novel; predictive modeling; programs; public health relevance; pyrethroid; resistance mechanism; scale up; screening; screening panel; success; sugar; tool; transmission process; vector; vector control; whole genome

Project Summary Malaria is a major cause of mortality and morbidity in Sub-Saharan Africa (SSA) and one of the biggest impediments to the economic development. The major method for controlling these malaria-transmitting mosquitoes is through the use of chemical insecticides but resistance has emerged and is a major threat to the recent reductions in both deaths and malaria infections. A major challenge facing malaria control program managers is knowing to what extent insecticide resistance is impacting control and when to take action eg by switching to a new intervention. In the first cycle of this award we exploited the advent of population genomic technologies to develop an improved understanding of the evolution and distribution of insecticide resistance mechanisms. In this proposal we describe how we will integrate this resistance marker discovery work with new functional genomic approaches and large vector control trials to demonstrate how genomic surveillance can be used to guide vector control. We will leverage our work on two large vector control trials in East Africa. In Uganda we embedded a cluster- randomised control trial (RCT) of long-lasting insecticidal nets (LLINs) with, and without, the synergist PBO into a countrywide distribution campaign. In Kenya together with KEMRI we are conducting an RCT of novel intervention, Attractive Targeted Sugar Baits. We will use whole genome sequencing of the three major malaria vectors Anopheles gambiae, An. funestus and An. arabiensis from these trial sites to identify genomic regions that are associated with insecticide resistance. We will then develop two contrasting models of the genetics of resistance. The first that assumes that we can accurately describe the likelihood of mosquito being insecticide resistant to by examining a small number of well characterised markers. This model capitalises on our recent developments in CRISPR/Cas9 transformation of Anopheles. The second model uses a polygenic score approach that requires a far larger number of markers, significantly-associated with resistance, but with no need for an understanding of causal mechanisms. By screening mosquito collections from the clusters within the RCTs and by, re-analysing the epidemiological data with the inclusion of the two resistance models, we will quantify the impact of resistance on the intervention efficacy. We will test whether the model based on a small number of genetic variants has sufficient predictive power for resistance monitoring or whether a larger number of loci provides superior predictive power. The former would aid widespread adoption of genetic surveillance of programmes. Finally through two modelling approaches we will 1. deliver predictions of molecularly-defined resistance at the administrative unit level in East Africa and 2. integrate these resistance data into transmission models of falciparum malaria to inform decisions on what is the optimal type of vector control to deploy.

项目总结

项目成果

Genome-wide association studies reveal novel loci associated with pyrethroid and organophosphate resistance in Anopheles gambiae s.l.

全基因组关联研究揭示了冈比亚按蚊 s.l 中与拟除虫菊酯和有机磷抗性相关的新位点。

• DOI: 10.1101/2023.01.13.523889
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Lucas,EricR;Nagi,SanjayC;Egyir-Yawson,Alexander;Essandoh,John;Dadzie,Sam;Chabi,Joseph;Djogbénou,LucS;Medjigbodo,AdandéA;Edi,ConstantV;Ketoh,GuillaumeK;Koudou,BenjaminG;Van'tHof,ArjenE;Rippon,EmilyJ;Pipini,Dimitra;Hard
• 通讯作者: Hard

Open source 3D printable replacement parts for the WHO insecticide susceptibility bioassay system.

用于 WHO 杀虫剂药敏生物测定系统的开源 3D 打印替换部件。

• DOI: 10.1186/s13071-019-3789-9
• 发表时间: 2019
• 期刊: Parasites & vectors
• 影响因子: 3.2
• 作者: Tomlinson S

Genome-wide association studies reveal novel loci associated with pyrethroid and organophosphate resistance in Anopheles gambiae and Anopheles coluzzii.

• DOI: 10.1038/s41467-023-40693-0
• 发表时间: 2023-08-16
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Lucas, Eric R.;Nagi, Sanjay C.;Egyir-Yawson, Alexander;Essandoh, John;Dadzie, Samuel;Chabi, Joseph;Djogbenou, Luc S.;Medjigbodo, Adande A.;Edi, Constant V.;Ketoh, Guillaume K.;Koudou, Benjamin G.;Van't Hof, Arjen E.;Rippon, Emily J.;Pipini, Dimitra;Harding, Nicholas J.;Dyer, Naomi A.;Cerdeira, Louise T.;Clarkson, Chris S.;Kwiatkowski, Dominic P.;Miles, Alistair;Donnelly, Martin J.;Weetman, David
• 通讯作者: Weetman, David

The genetic architecture of target-site resistance to pyrethroid insecticides in the African malaria vectors Anopheles gambiae and Anopheles coluzzii.

• DOI: 10.1111/mec.15845
• 发表时间: 2021-11
• 期刊: MOLECULAR ECOLOGY
• 影响因子: 4.9
• 作者: Clarkson, Chris S.;Miles, Alistair;Harding, Nicholas J.;O'Reilly, Andrias O.;Weetman, David;Kwiatkowski, Dominic;Donnelly, Martin J.
• 通讯作者: Donnelly, Martin J.

Wolbachia endosymbionts in two Anopheles species indicates independent acquisitions and lack of prophage elements.

• DOI: 10.1099/mgen.0.000805
• 发表时间: 2022-04
• 期刊: MICROBIAL GENOMICS
• 影响因子: 3.9
• 作者: Quek, Shannon;Cerdeira, Louise;Jeffries, Claire L.;Tomlinson, Sean;Walker, Thomas;Hughes, Grant L.;Heinz, Eva
• 通讯作者: Heinz, Eva