The role of chemosensory proteins in conferring pyrethroid resistance

Insecticide resistance is a major threat to global health and food security. Globally, vector borne diseases account for more than 17% of infectious disease annually, with over half the world’s population currently at risk. Similarly, around 35% of all crops are lost to pre-harvest pests while pressure on increased agricultural output is growing due to an ever-expanding population size. Both vector control and agricultural pest management rely heavily on the use of pesticides. The efficacy of insecticide control is exemplified by the success of malaria control programmes in Africa which have been heavily dependent on the use of pyrethroid insecticides in bednets. As with intensive use of any drug or pesticide, the target organisms (in this case Anopheles mosquitoes), have developed widespread resistance to the chemicals used to control them (in this case pyrethroid insecticides), posing a critical threat to the future of malaria control.

Recent discovery has identified a highly potent pyrethroid resistance mechanism in African Anopheles mosquitoes. An increase in the expression of a class of small proteins normally involved in chemical communications (and hence termed chemosensory proteins) in the legs of the mosquito acts as a sponge, absorbing the pyrethroid insecticides as it enters the mosquito via contact with the bednet. One specific member of this protein family, SAP2, is of key importance: mosquitoes that have elevated levels of SAP2 have a much greater chance of surviving pyrethroid exposure and, if we stop the mosquitoes producing this protein, this pyrethroid resistance largely disappears. This latter observation is remarkable as the mosquito populations tested contain additional well established resistance mechanisms including structural changes in the pyrethroid target site that reduce insecticide binding and elevated levels of enzymes that detoxify pyrethroids in the mosquito; the finding that silencing a single small protein can revert these mosquitoes to pyrethroid susceptibility opens up the exciting prospect that we may have found a way of blocking pyrethroid resistance in the mosquito, and potentially other pest species.

In the first part of this proposal we will establish exactly how increases in expression of this SAP2 protein plays such a pivotal role in pyrethroid resistance. In the remaining sections, we will develop methods to break this resistance mechanism; we have already developed a biological test to identify chemicals that block SAP2. Here we propose to convert this to a higher throughput tool that will be used to screen existing libraries of thousands of chemicals to identify potential compounds that could be developed into additives to be used in combination with pesticides to block this resistance mechanism and restore full efficacy of pyrethroid insecticides.

Biotechnology and Biological Sciences Research Council (BBSRC) project details

Enabling Technologies & Assays
Insecticide Resistance
Vector Control

Mar 2021 — Mar 2024

$632,000

United Kingdom