The global burden of malaria has led to the development of multiple approaches to reduce its incidence through targeting it’s vector, Anopheles mosquitoes. These measures include reducing vector breeding grounds, using biological controls such as lavivorous fish to decrease larvae numbers, and chemical spraying of insecticides such as pyrethroids and DDT (dichlorodiphenyltrichloroethane). However, the widespread use of these insecticides has led to the development of resistant vectors. Charles Wondji and Janet Hemingway from the Liverpool School of Tropical Medicine, UK, and colleagues reveal the first genetic marker for metabolic resistance to DDT in their recent study in Genome Biology. Wondji and Hemingway explain the implications of their results for tracking and managing vector resistance.
What first got you interested in mosquito genomics?
Our interest in mosquito genomics started when we realised the power of this approach in elucidating the underlying molecular basis of various genetic traits in mosquitoes, notably that of insecticide resistance in disease vectors. The sequencing of the first mosquito genome in 2002 was a major encouragement to further explore this field of research.
Were there any surprises for you in the results of the current study?
Yes, the big surprise for us was the discovery that a single amino acid change alone in a detoxification gene could have such a dramatic impact on metabolic resistance to insecticides in a mosquito species. This type of resistance is normally associated with increased transcription of detoxification genes, not single amino acid changes. In addition, we were also surprised by the extent of the selection footprint in resistant mosquitoes with the resistance allele having reached fixation in the highly DDT resistant population from Benin.
How does this study fit in with your previous work?
The two major causes of pyrethroid and DDT resistance are target-site insensitivity and metabolic resistance. Target-site resistance (also known as knockdown resistance) has previously been well characterised and can be easily monitored by PCR. However, this was not possible for metabolic resistance, despite its greater operational impact on malaria control, due to its complex molecular basis. No single metabolic resistance markers were available to track resistance in malaria vectors; consequently, there was no DNA-based diagnostic tool to easily detect metabolic resistance in field populations, in contrast to target-site resistance. This study provides the first step in generating DNA diagnostics for metabolic resistance.
What do you think the practical applications are for mosquito control in the field?
This study, for the first time, has defined a molecular marker for metabolic resistance, the type of resistance which is most likely to lead to control intervention failure against mosquito-transmitting malaria. This marks significant progress as the first DNA-based diagnostic tool has now been designed for this type of resistance. Such tools are needed to detect and track resistance at an early stage in field populations, allowing control programs to design rational, evidence-based resistance management strategies to overcome such resistance and maintain the efficacy of vector control interventions such as Indoor residual spraying (IRS) or Long Lasting Insecticide Nets (LLINs).
In addition, this study is a proof of concept that similar types of metabolic resistance in other disease vectors could also be elucidated and the relevant DNA-based diagnostic tools designed to improve ongoing and future control programs. In the case of malaria, this will fulfil one of the key goals of the recent WHO Global Plan for Insecticide Resistance Management (GPIRM).
You mention in your study that Southern Africa has a low incidence of the DDT resistance mutation. Can you foresee a time when controlled use of DDT will be reintroduced in countries where it is currently banned, perhaps as pyrethroid resistance increases?
Pyrethroid resistance observed in South Africa around 1999 was suspected to have caused a significant increase in malaria transmission in this country. The solution then was to re-introduce DDT because of the full susceptibility in malaria vectors and as a result these mosquitoes were again successfully controlled and malaria transmission significantly decreased. We therefore believe that due to the high and rapid spread of pyrethroid resistance currently observed in Africa (and resistance to other alternative insecticide classes such as carbamates), DDT if used in a controlled way can serve as a last resort insecticide to save lives in countries where DDT remains very efficient against major malaria vectors.
Is complete eradication of malaria-transmitting mosquitoes feasible or desirable? If so, will chemical spraying play a part in how this is achieved?
We don’t believe that a complete eradication of malaria-transmitting mosquitoes is possible due to their diverse and plastic ecology, biology and genetics. Indeed, these mosquitoes are able to exploit various types of breeding sites, exhibit extensive behavioural and genetic plasticity that will make their complete eradication virtually impossible. This is why the aim is rather to control these mosquitoes to the extent that malaria transmission could be interrupted. Vector control through the use of chemical spraying plays an important part in this aim but other approaches are also explored such as larval management or transgenic methods.
Are there any unanswered questions you would like to investigate?
The genetics basis of many insecticide resistance mechanisms remains uncharacterised and we are currently working on this. Besides this, establishing the real impact of insecticide resistance on malaria mortality and morbidity and how best to mitigate such impact is of great interest in the fight to reduce the burden of this disease. Design of more reliable diagnostic tools will be a significant contribution towards answering such important questions.