ir-tex-an-open-source-data-integration-tool-for-big-data

IR-TEx: An Open Source Data Integration Tool for Big Data Transcriptomics Designed for the Malaria Vector <em>Anopheles gambiae</em>

IR-TEx is an application written in Shiny (an R package) that allows exploration of the expression of (as well as assigning functions to) transcripts ...

Liverpool School of Tropical Medicine

liverpool school of tropical medicine

The elevated expression of enzymes with insecticide metabolism activity can lead to high levels of insecticide resistance in the malaria vector, Anopheles gambiae. In this study, adult female mosquitoes from an insecticide susceptible and resistant strain were dissected into four different body parts. RNA from each of these samples was used in microarray analysis to determine the enrichment patterns of the key detoxification gene families within the mosquito and to identify additional candidate insecticide resistance genes that may have been overlooked in previous experiments on whole organisms.

Dissecting the organ specificity of insecticide resistance candidate genes in Anopheles gambiae: known and novel candidate genes.

Malaria control in Africa is dependent upon the use insecticides but intensive use of a limited number of chemicals has led to resistance in mosquito populations. Increased production of enzymes that detoxify insecticides is one of the most potent resistance mechanisms. Several metabolic enzymes have been implicated in insecticide resistance but the processes controlling their expression have remained largely elusive.

The transcription factor Maf-S regulates metabolic resistance to insecticides in the malaria vector Anopheles gambiae.

Increasing insecticide resistance in malaria-transmitting vectors represents a public health threat, but underlying mechanisms are poorly understood. Here, a data integration approach is used to analyse transcriptomic data from comparisons of insecticide resistant and susceptible Anopheles populations from disparate geographical regions across the African continent. An unbiased, integrated analysis of this data confirms previously described resistance candidates but also identifies multiple novel genes involving alternative resistance mechanisms, including sequestration, and transcription factors regulating multiple downstream effector genes, which are validated by gene silencing. The integrated datasets can be interrogated with a bespoke Shiny R script, deployed as an interactive web-based application, that maps the expression of resistance candidates and identifies co-regulated transcripts that may give clues to the function of novel resistance-associated genes.

Transcriptomic meta-signatures identified in Anopheles gambiae populations reveal previously undetected insecticide resistance mechanisms.

Insecticides formulated into products that target Anopheles mosquitos have had an immense impact on reducing malaria cases in Africa. However, resistance to currently used insecticides is spreading rapidly and there is an urgent need for alternative public health insecticides. Potential new insecticides must be screened against a range of characterized mosquito strains to identify potential resistance liabilities. The Liverpool School of Tropical Medicine maintains three susceptible and four resistant Anopheles strains that are widely used for screening for new insecticides. The properties of these strains are described in this paper.

Characterisation of Anopheles strains used for laboratory screening of new vector control products.

Pyrethroid-impregnated bed nets have driven considerable reductions in malaria-associated morbidity and mortality in Africa since the beginning of the century. The intense selection pressure exerted by bed nets has precipitated widespread and escalating resistance to pyrethroids in African Anopheles populations, threatening to reverse the gains that been made by malaria control. Here we show that expression of a sensory appendage protein (SAP2), which is enriched in the legs, confers pyrethroid resistance to Anopheles gambiae. Expression of SAP2 is increased in insecticide-resistant populations and is further induced after the mosquito comes into contact with pyrethroids. SAP2 silencing fully restores mortality of the mosquitoes, whereas SAP2 overexpression results in increased resistance, probably owing to high-affinity binding of SAP2 to pyrethroid insecticides. Mining of genome sequence data reveals a selective sweep near the SAP2 locus in the mosquito populations of three West African countries (Cameroon, Guinea and Burkina Faso) with the observed increase in haplotype-associated single-nucleotide polymorphisms mirroring the increasing resistance of mosquitoes to pyrethroids reported in Burkina Faso. Our study identifies a previously undescribed mechanism of insecticide resistance that is likely to be highly relevant to malaria control efforts.

Article	Year
Dissecting the organ specificity of insecticide resistance candidate genes in Anopheles gambiae: known and novel candidate genes. BMC genomics\| PubMed ID: 25421852	2014
The transcription factor Maf-S regulates metabolic resistance to insecticides in the malaria vector Anopheles gambiae. BMC genomics\| PubMed ID: 28854876	2017
Transcriptomic meta-signatures identified in Anopheles gambiae populations reveal previously undetected insecticide resistance mechanisms. Nature communications\| PubMed ID: 30538253	2018
Characterisation of Anopheles strains used for laboratory screening of new vector control products. Parasites & vectors\| PubMed ID: 31690332	2019
A sensory appendage protein protects malaria vectors from pyrethroids. Nature\| PubMed ID: 31875852	2020

Victoria A. Ingham

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