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

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Infectious and Tropical Diseases

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Jones RT (2021) Novel control strategies for mosquito-borne diseases. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

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Martinez J (2021) Differential attraction in mosquito-human interactions and implications for disease control. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

 
Title Project Logo 
Description We created a project logo using digital drawing and deposited it on the project website. 
Type Of Art Artwork 
Year Produced 2017 
Impact There is no notable impact that we are aware of. 
URL https://www.lshtm.ac.uk/genoscent#welcome
 
Description We have demonstrated that attractiveness to Anopheles mosquitoes is heritable. This is the first report of this. We have also begun the genetic analysis and showed that the HLA (MHC) does not appear to be involved contrary to a previous publication which suggested it was. We are now doing a wider genome association study to identify genes associated with attractiveness.
Exploitation Route This will open up further studies into the mechanisms of why some people attract more malaria mosquitoes than others. The findings will also be useful for mathematical modelling and epi studies interested in population susceptibility to malaria.
Sectors Healthcare

 
Description We have had significant interaction with the media including BBC and various other public facing outlets over the last two years. This includes science festivals such as the Big Bang and the Royal Society Summer Science exhibition this year.
First Year Of Impact 2018
Sector Healthcare
Impact Types Cultural

 
Description Microbiomics and genetics of human attractiveness to malaria mosquitoes
Amount £100,000 (GBP)
Funding ID 2083516 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2018 
End 09/2022
 
Description Partnership with MRCG 
Organisation Medical Research Council (MRC)
Department MRC Unit, The Gambia
Country Gambia 
Sector Public 
PI Contribution Study design and training
Collaborator Contribution Partners will recruit and consent study participants, taking advantage of expertise in this area. Trained teams will collect samples, and do sample testing in the laboratory. DNA extraction robot will be utilized.
Impact Collaboration involves malaria and molecular laboratories at MRCG,
Start Year 2019
 
Description Entomology symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Research progress to date presented at a public health in entomology symposium
Year(s) Of Engagement Activity 2019
 
Description Malaria Center Newsletter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact We advertise our project in the monthly newsletter of the Malaria Center. The Malaria center is based at the London School of Hygiene and Tropical Medicine (LSHTM) and facilitates interdisciplinary research at the School as well as supports and promote links with research in malaria endemic countries. The Centre brings together around 300 researchers, postgraduate students and support staff from all 3 faculties in LSHTM.
Year(s) Of Engagement Activity 2017
URL http://malaria.lshtm.ac.uk/
 
Description Project website 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact We created a webpage describing our project and our team on the London School of Hygiene and Tropical Medicine website. The webpage includes URL links to our collaborators as well as an educational video presenting our pilot study that was previously deposited on Youtube (https://www.youtube.com/watch?v=8Es9SUECPlc).
Year(s) Of Engagement Activity 2017
URL https://www.lshtm.ac.uk/genoscent
 
Description Science festivals / events 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact We have attended four science events with an interactive exhibit demonstrating the science behind the project. It reached an audience of thousands and stimulated many conversations (e.g. Big Bang, Science Museum's Lates, Destinations Show, British Science Association's festival).
Year(s) Of Engagement Activity 2017,2018