The mechanisms underlying the production of natural mosquito repellents by human beings

Some human beings are bitten more than others by mosquitoes. From an evolutionary perspective this is fundamentally important since those that get bitten less often are less likely to die from lethal mosquito-borne diseases like malaria. Thus there is likely to be a selective advantage for being less attractive to malaria mosquitoes. Whether or not this is due to natural selection in humans, or because mosquitoes are simply avoiding unsuitable hosts is unknown, but our previous studies show that human differential attractiveness to mosquitoes is due to the natural production of key repellent chemicals given off by individuals who rarely get bitten. Essentially this could be thought of as the first line of defence related to the immune system. In a recent pilot study we showed that for Europeans how attractive you are to mosquitoes is controlled by your genes. We intend to extend this line of research and carry out a similar study amongst an indigenous African population that has traditionally been under intense selective pressure from malaria. Here we would anticipate finding genes for new repellent molecules that are under selection. The natural repellent chemicals that we have identified from our study of Europeans are effective repellents when applied to the skin, but what remains unknown is how the body produces these chemicals and which genes control this process. Preliminary studies show that some of the repellents can be produced by skin cells and there are likely candidate genes as potential targets. In this study we aim to compare identical and non-identical twins using chemical ecology and molecular genetic techniques to identify how the chemicals are produced and which genes are involved in production and regulation. This will give an understanding of how the body provides an important component of natural resistance to mosquitoes and provide a new potential treatment which stimulates production of these repellent chemicals in susceptible human beings. This could allow us to develop a more persistent application and eventually an oral treatment in the form of a pill which enhances the production of natural repellents to protect against mosquito bites, minimising the need for repeated skin-applied volatile repellents. This research has the potential to find new mosquito repellents that could be produced systemically, and elucidate one of the least understood innate immunity mechanisms: how we use chemical warfare to hide from vectors.

One of the most effective protections against outdoor-biting mosquitoes is from skin-applied repellents. Whilst repellents have been shown to reduce malaria transmission in some studies, they pose problems for control programmes because people do not use repellents properly and they lack persistence, making them a difficult intervention to exploit. A new generation of personal protection is needed which eliminates the need for application to the skin. Many people report that they are highly prone, or unusually resistant, to being bitten by mosquitoes and we have shown that this is due to differences in chemicals produced in our body odour. Individuals that attract few mosquitoes produce natural, volatile repellent compounds that repel mosquitoes. These chemicals provide complete protection against mosquito bites and are now being developed as products. However, the mechanisms underpinning the production of the repellents by the human body have not yet been elucidated. In a recent pilot study, we demonstrated that attractiveness to mosquitoes is controlled by genetic factors. There is now an exciting opportunity to investigate the genes associated. Our aim is to understand the genetic mechanisms underlying differential attractiveness and determine its biomedical potential to reduce disease transmission. We hypothesise that differential repellency between individuals is mediated by genes that control the production of volatile repellents through the skin. Using cohorts of identical and non-identical twins we will investigate and identify genes that are associated with attractiveness to mosquitoes and those that control the production of natural repellents. In the long term, this could lead to the development of novel small molecules (potentially in pill-form) that enhance the production of natural repellents by the human body, thus eliminating the need for topical application of repellents to the skin, benefitting people at risk of mosquito-borne diseases.

The technologies generated from this project have the potential to increase the competitiveness of the UK. With current vector control tools facing problems such as insecticide resistance, and, with the exception of GM and Wolbachia for Aedes mosquitoes, little to no development of novel interventions since the use of bed nets, we believe protection against vector borne disease is in need of transformation. Our project could fulfil this need and would give the UK a boost in this scientific field and contribute greatly to the UK science base. Although there is evidence that mosquitoes will bite some people more than others the underlying mechanisms responsible for the production of host odours have hardly been studied. We propose to examine the human- Anopheles gambiae s. s. mosquito system, one of the most important systems in the context of humanity, with malaria causing over 200 million human malaria cases, and having a negative impact on the economic growth of the countries affected. The information generated in this project will be ground breaking and could lead to the development of "game-changing" novel control technologies that will benefit the health and wellbeing of large populations who live in or travel to disease endemic countries. The development of a novel drug for the prevention of biting by insects would be of benefit to the pharmaceutical industry and could redefine the disease control sector as well as the travel health market. In the short term (within the next 2-4 years) we may identify novel semiochemicals including attractants or repellents which could be exploited to improve conventional products such as traps and conventional repellents which would of interest to potential licensees from industry. The identification of such technologies could improve the health of travellers and local people in mosquito-borne disease endemic countries. To exploit the technologies commercially, we will use the established expertise and contacts. We will publish our findings in high impacting, open access journals. Some knowledge from our study may enable epidemiologists to improve mathematical models. Including more accurately the biting rate in the models will increase the reliability and therefore the impact of mosquito control strategies that are implemented based on the predictions of the models. Government agencies may use this information to make decisions about policies relating to current vector control programmes. If a product is developed governments (from disease endemic countries and those with people who travel) regulatory authorities including the UK's Health and Safety Executive, and the World Health Organisation, as well as numerous charities and NGOs will be interested in the outcome of this study as it will give information to control programmes about risk of being bitten, and hence transmission, in a disease endemic region for many diseases like malaria, dengue and Zika. Such a technology could be distributed to local populations as has happened for bed nets and could change policy in terms of recommendations for control of vector-borne diseases and may allow practitioners to offer better advice to travellers. The project will generate new skills and knowledge and will establish collaborations between the applicants extending beyond the proposed project. Since the work itself is pioneering and of public interest it is likely to spark interest from museums and festivals, for example, the Science Museum and the Natural History Museum. We have already been invited to give a public talk at the Science Museum Lates on the topic of "A mosquito repellent cloak". Dr Logan is the Chief Scientific Advisor to Pestival - a £5 million arts and science festival supported by the Wellcome Trust which will run in 2018. An interactive display about this project is planned for the "Entomophobia" Zone. Wherever appropriate, efforts will be made to communicate to the public and other beneficiaries through the media.