Molecular characterization of insecticide resistance and transmission competence in sand flies, major vectors of leismaniasis

Leishmania, transmitted by sand flies, comes second only to malaria in terms of parasitic causative fatalities globally. Tunisia, as well as the Mediterranean region are endemic for the disease, reporting hundreds of cases annually. In the absence of human vaccines, controlling the population size of sand flies using insecticides is a key component of leishmaniasis control efforts. Nevertheless, the reliance on insecticides has triggered the selection of resistance, which is threatening the efficacy of sand fly vector control programs. The molecular aetiology behind the insecticide resistance status of sand flies, unlike other insect vectors, remains largely unknown. The aim of LeVec is to unravel the mechanisms that underpin resistance to pyrethroid insecticides in sand fly populations, collected in Tunisia. I will use comparative transcriptomic analysis to identify genes differentially expressed in resistant individuals and functionally validate their role using state of the art in vitro (biochemical assays) and in vivo (transgenesis and CRISPR genome editing) approaches. The outcomes will substantially improve our ability to track the phenomenon of sand fly resistance in the field and design mitigation strategies. Furthermore, LeVec aims to identify genes that determine the ability of sand flies to transmit the Leishmania parasites. For that I will focus on the sand flys midgut, the site where the complete development of the Leishmania parasites takes place, and perform comparative expression analysis, using a unique collection of 12 sand fly species with different degrees of vector competence. Silencing of candidate genes followed by experimental infections will allow me to validate their role in Leishmania transmission. The outcomes of this analysis will help the design of novel Leishmania control tools, based on disrupting the adherence and/or development of parasites within the sand fly vector.