Epidemiological consequences of reproductive senescence in a long-lived vector

Lead Research Organisation: University of Bristol
Department Name: Biological Sciences

Abstract

Tsetse flies transmit single-celled parasites - trypanosomes - to livestock with a single infectious bite. Once infected, the animal develops animal African trypanosomiasis (AAT), a fatal disease which kills 1-2 million cattle and costs sub-Saharan Africa 3-5 billion USD in lost agricultural potential each year. Strategies to control this disease are informed by mathematical models describing rates of parasite transmission between tsetse and hosts and changes in the numbers of tsetse.

A crucial aspect of an insect's ability to transmit a disease-causing parasite is its longevity and susceptibility to infection. For a wide variety of animals, longevity and susceptibility to infection are affected by the investment made by an individual's mother. This maternal effect is likely to be very important for tsetse because of their unusual reproductive biology. Unlike most other insects, female tsetse get pregnant, lactate and give birth to live young, which weigh more than the mother. Tsetse can survive over six months in the field with females producing a single larva every ~10 days. The close link between an individual fly and its mother suggests that there will be a marked maternal effect on tsetse longevity and immunity and hence parasite transmission. Models for trypanosomiasis are based on the Ross-Macdonald model for human malaria, however, and do not consider the role of maternal investment in tsetse population dynamics or epidemiology as malaria mosquitoes - like most other vectors - reproduce through egg laying.

This project will investigate how maternal investment changes with age and nutrition in tsetse, the consequences for offspring survival and ability to spread trypanosomes, and the contribution of these processes to tsetse population and disease transmission dynamics. We will conduct parallel observations of tsetse in the laboratory - using a large colony of flies at the Liverpool School of Tropical Medicine - and in the field, using flies of estimated age caught using an innovative sampling method in their natural habitat in Zimbabwe. We will experimentally manipulate nutrition in females and measure the costs of reproduction by preventing females from mating until they are older, to assess whether late-life declines in reproductive output (such as those reported in humans) reflect depleted resources or build-up of damage as a by-product of reproduction. We will develop new evolutionary models to understand whether such patterns represent adaptive strategies to maximize the total number of offspring produced in a lifetime, constraints due to physiology, or a combination of these processes.

We will follow offspring born to mothers of varying age and nutritional state to test whether offspring born to older or nutritionally stressed mothers are more likely to die young or become infected by trypanosomes. We will also test whether maternal effects are stronger in sons than daughters.

Finally, we will use insights from these experimental observations and evolutionary models to improve epidemiological models predicting the spread of tsetse-borne diseases. These diseases can persist at low prevalence and vector density, only to flare up when control efforts are relaxed or new habitats become suitable. Our new models will be used to predict the role of mothers in helping tsetse populations to persist or shift range as a result of human-related and environmental change. The accuracy of these models will be validated against existing data on the distribution and abundance of tsetse, their hosts and disease prevalence.

Technical Summary

Epidemiological and demographic models are essential for predicting and mitigating risks of vector-borne diseases to livestock and humans, including animal African trypanosomiasis (AAT), which is transmitted by tsetse flies. We hypothesize that failure to consider maternal investment and reproductive senescence in tsetse has limited the accuracy of models for animal trypanosomiasis.

Our aim is to improve models of tsetse population and disease dynamics, through the following objectives:
1. Establish how maternal investment changes as female tsetse age;
2. Measure the effects of maternal investment on offspring lifespan and capacity to transmit disease;
3. Elucidate how maternal effects influence tsetse population and disease dynamics.

We will achieve these objectives by combining empirical observations with evolutionary and epidemiological models. First, we will measure fat transferred by mothers to offspring, using laboratory flies of known ages and age-estimated wild flies from Zimbabwe. We will experimentally manipulate female nutrition and costs of reproduction in laboratory flies to establish the physiological determinants of age-dependent patterns. We will develop evolutionary models to ascertain whether maternal investment reflects adaptive decisions or physiological constraints.

Second, we will monitor offspring born to mothers of varying nutrition and age to establish how maternal effects influence offspring size, lifespan and reproductive success. We will infect offspring with trypanosomes to measure how maternal investment influences offspring competence at spreading disease.

Lastly, we will incorporate empirical findings into models of tsetse population and disease dynamics, using differential equation models and agent-based simulations. These models will be validated using data on tsetse abundance, host densities and trypanosome prevalence, to predict the spread of tsetse-borne disease as new habitats become suitable for this vector.

Planned Impact

Livestock keepers and communities in tsetse-suitable areas. This project will improve efforts against animal African trypanosomiasis (AAT). Some 10 million km2 of sub-Saharan Africa, covering 37 countries, are infested with tsetse and effective control of AAT could benefit people within this area. There is currently no vaccine for AAT and the only means of mitigating the disease are through tsetse control and use of trypanocides. Reducing the incidence of AAT through vector control improves cattle productivity and, ultimately, reduces poverty; currently, the loss of livestock to AAT causes annual economic losses of $4 billion. Healthier herds will improve the functioning of livestock as stores of value and indicators of social status contributing to the natural, financial and social capital of affected communities.

Policymakers in tsetse control. The project has close links to the Tsetse Control Division in Zimbabwe and outputs from our project will inform their monitoring and control efforts directly. Thus, if our project shows that maternal nutritional stress increases tsetse offspring's susceptibility to disease, our models will highlight the need for increased surveillance and trapping in areas affected by drought for several months after conditions improve, to account for carryover effects across generations. Several members of the team (Torr, Hargrove, Vale, Keeling) have strong links to national, regional and international organisations (e.g. WHO, FAO), private companies (e.g. Vestergaard, CEVA) and donors (BMGF) concerned directly with developing, supporting and implementing interventions against human and animal trypanosomiases. Outputs from this project will contribute to the knowledge that underpins the policy and practice of trypanosomiasis control being developed by these organisations.

General public. Our project is not just about predicting tsetse-borne disease, but, more broadly, understanding the profound effects that mothers can have on their offspring. This will capture the interest of the general public, as it is not generally known that tsetse - like mammals - ovulate, can get pregnant and also lactate, and thus serve as an evolutionary model of pregnancy. As an example, our project will produce evolutionary explanations for why - in a system such as mammals and tsetse, where mothers invest enormously in each offspring - mothers terminate in utero development when they are nutritionally stressed. The enormous difference between tsetse and humans notwithstanding, these few but remarkable points of similarity mean that results of our project will be of interest to our society in which maternal under- and over-nutrition is of concern, and where women are waiting until much later in life to start reproducing.
 
Description Global Challenges Pump-Priming Call
Amount £26,700 (GBP)
Organisation University of Bristol 
Sector Academic/University
Country United Kingdom
Start 02/2018 
End 07/2018
 
Description Industrial and International Leverage Fund (part of EPRSC DTP award)
Amount £38,062 (GBP)
Organisation University of Bristol 
Sector Academic/University
Country United Kingdom
Start 01/2021 
End 07/2024
 
Description International Strategic Fund: "The interactive effect of maternal nutrition and microbiome on offspring immunity and fitness"
Amount £2,730 (GBP)
Organisation University of Bristol 
Sector Academic/University
Country United Kingdom
Start 01/2020 
End 08/2020
 
Description Janet Hemingway Fellowship
Amount £0 (GBP)
Organisation Liverpool School of Tropical Medicine 
Sector Academic/University
Country United Kingdom
Start 07/2020 
End 07/2023
 
Description Public Engagement Fund
Amount £5,480 (GBP)
Funding ID PEF\R3\3011 
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2020 
End 04/2022
 
Description UKRI Covid-19 Grant Extension Allocation (CoA)
Amount £27,875 (GBP)
Organisation United Kingdom Research and Innovation 
Sector Public
Country United Kingdom
Start 03/2021 
End 09/2021
 
Description You are what your mother eats: understanding mother-offspring interactions in tsetse vectors of disease.
Amount £93,344 (GBP)
Funding ID 2266363 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2019 
End 09/2023
 
Title Method for individual housing of tsetse flies 
Description The technician funded by our BBSRC project developed a new method for housing individual tsetse in such a way that does not interfere with their feeding and minimises effect on mortality: previous efforts to house flies individually tend to have higher mortality because flies feed better when housed together. 
Type Of Material Biological samples 
Year Produced 2020 
Provided To Others? No  
Impact The impact generated has been the ability to track the reproductive output of individual female flies, which is key for testing predictions of reproductive senescence, and will also be useful in future studies manipulating breeding the condition or environment of breeding females and measuring output for their offspring. Note that full details of the method will be published as a supplementary file alongside our paper on the experimental results (currently under review). 
 
Description SACEMA 
Organisation University of Stellenbosch
Department South African Centre for Epidemiological Modelling and Analysis
Country South Africa 
Sector Academic/University 
PI Contribution I have provided intellectual input in interpreting data analysis and helping to draft a manuscript.
Collaborator Contribution My partner has provided data on tsetse maternal investment and the opportunity to co-author a paper on maternal investment in wild tsetse. Results from this study form important background to our work on how maternal investment changes with age, and we are continuing data collection at the same study site in Zimbabwe.
Impact Publication: doi: 10.1098/rsos.171739
Start Year 2014
 
Description Advanced Science News blog 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact We were invited to write a popular science article based on our review published in BioEssays, which along with press releases for our article, facilitated the review having a wide reach (an Altmetric score of 74 - in the top 5% of outputs - with 65 tweets, across 9 countries).
Year(s) Of Engagement Activity 2020
URL https://www.advancedsciencenews.com/meet-the-tsetse-fly-the-supermom-of-the-insect-world/
 
Description Article in Bristol Student Newspaper 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact An article about our BioEssays review was written by a Paleobiology Master's student, Alex Lawrence, and published in Epigram, the University of Bristol's Independent Student Newspaper. As there is no comments section in this newspaper it is difficult to estimate the impact, but given that the paper has almost 6,000 followers it is likely to have a wide reach across the University student community and beyond.
Year(s) Of Engagement Activity 2020
URL https://epigram.org.uk/2020/12/05/the-insect-mothers-that-give-birth-to-babies-as-large-as-themselve...
 
Description BBC Radio Merseyside feature interview for SciFri 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Dr Lee Haines (co-investigator at LSTM) was interviewed by Tony Snell about working with the largest breeding colony of tsetse flies in the UK. This interaction with the BBC staff resulted in her being asked if she would like to be the designated entomology specialist for the station. She agreed and was invited back to discuss a) the unprecedented midge outbreak in Scotland and what personal protection is advisable to use (June 11, 2018) and b) the practice of entomophagy in relation to Sainsbury's release of cricket chips and the I'm a Celebrity challenge (Nov 26, 2018).
Year(s) Of Engagement Activity 2018
URL https://www.lstmed.ac.uk/news-events/news/scifri-on-bbc-radio-merseyside
 
Description FutureLearn Vector-Borne Disease course 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Dr Lee Haines (LSTM) from our team contributed a lecture on the biology of tsetse flies for a freely available, massive online-open course on vector-borne disease, hosted on the FutureLearn website and developed as part of an initiative between the London School of Hygiene & Tropical Medicine (LSHTM) and its ARCTEC team, the Innovative Vector Control Consortium (IVCC) and LSTM. Her lecture received almost 70 positive comments from course attendees. The course has had over 4000 people enrolled across the world including many lower and middle income countries, and it has received an overall review score of 4.8/5.
Year(s) Of Engagement Activity 2020
URL https://www.futurelearn.com/info/press-releases/new-online-course-launched-on-the-control-of-vector-...
 
Description Hosted class of Art in Science students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Hosted a class of Art in Science students (at Liverpool John Moores University) and discussed tsetse and its unique life history in terms of art and how to revisit science with artistic eyes. This is part the teaching curriculum where art students, oftentimes scientific illustrators, have a chance to interact with scientist. A few tsetse were brought out on display as well.
Year(s) Of Engagement Activity 2019
 
Description Interview on Bristol University Radio Station (BURST) NatureXposed programme 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Dr Sinead English was interviewed by two Bristol postgraduate students, Amy and Benito, who host a radio programme called Nature Xposed which covers different topics in natural history each week. She discussed why she was interested in tsetse life history strategies, and in particular the role of maternal investment in this unusual disease vector, during an interview which was interspersed with 'tsetse-inspired' music including songs about the tsetse fly as well as about mothers. She gave a broad explanation of the main aims of the BBSRC-funded project and discussed the link between studying flies in the wild, conducting experiments in the lab and developing predictive models. The presenters said it was one of the most popular episodes of their show with a high number of downloads afterwards, and that they personally were fascinated by the fact that these flies gave birth to live young - something they had not realised before planning for the show. On hearing the interview, another broadcaster contacted Sinead to express enthusiasm to interview her for a podcast which explores the link between biology and the law.
Year(s) Of Engagement Activity 2018
URL https://www.mixcloud.com/benitowainwright/dr-sinead-english-tsetse-flies-and-meerkats/
 
Description Liverpool LASER (Leonardo Art Science Evening Rendezvous) at the TATE 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The Perception Machine was a working studio-laboratory at Tate Exchange presented by LJMU's MA Art in Science programme, bringing together artists and scientists to discover where our mutual interests intersect. It was a space to explore and engage with new interpretations of selected artworks on display in the first floor galleries at Tate Liverpool. Some of Liverpool's leading scientists worked with us to explore overlooked or hidden details of familiar works. Their particular 'lenses' of experience reveal unexpected insights.

The Perception Machine was supported by a Liverpool LASER (Leonardo Art Science Evening Rendezvous) event that asked a group of artists and scientists to speak on their perceived role of art in science, and science in art. During 'The Perception Machine' LASER our speakers used their own research and experiences to discuss the possibilities that arise from Art and Science collaborations. Dr Lee Haines (co-investigator at LSTM) gave a talk in this event, which was streamed on YouTube for a wider audience: https://www.youtube.com/watch?v=rKaZkHSf4ow&list=PLD_jFJJqLKxLRm5lyKEGT0x5e66MjEIcn?dex=4&t=0s

Most significant impacts: expanded collaboration with MA students at John Moores, invited to participate in MA Art in Science 7001MAAS Studio Practice module showcasing tsetse reproduction and introducing concepts of senescence and impact of climate change on the species (Nov 27, 2018). Have been invited to participate in the organisation of a series of events which cross Arts and Science at the Keller III gallery in Hannover (Germany) and two German art grants have now been submitted to the German funding bodies. The main aim of this event would be to bring down the "big invisible wall" between the wider audience, artists and scientists, using lectures, hands-on activities, music concerts and art projects as platforms. Scientists confirmed to contribute are all from University of Oxford and include Prof. Matthew Freeman, the head of the Sir William Dunn School of Pathology, Prof. Ulrike Gruneberg from the Dunn School, and Dr. Richard Wheeler from the Nuffield Department of Medicine. If this goes forward (we´ll know in end February/mid March) a group of artists and Hannover local scientists would meet at the Keller III on the weekend of 4th/5th May 2019 to discuss ideas so that the artists could work on a piece inspired in this meeting/workshop. The artistic outcome would be presented at the final exhibition from 14th September to 6th October later this year.
Year(s) Of Engagement Activity 2018
URL https://www.lstmed.ac.uk/news-events/events/lstm%E2%80%99s-dr-lee-haines-at-liverpool-laser-tate-liv...
 
Description Mini-documentary on YouTube 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact A professional film-maker created a short documentary to describe our project aims - to understand tsetse reproductive ecology, senescence and link to disease transmission - and our international and interdisciplinary approach. This was released on YouTube around the time of one of the major review papers from our project (31 October 2020), and has been viewed 290 times.
Year(s) Of Engagement Activity 2020
URL https://www.youtube.com/watch?v=2-dekOKCoRA
 
Description Mosquitoes to Microbes Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact The workshop involved setting up a pop-up science lab within the centre to showcase tsetse flies and other insects under the microscope and in display cases, swabbing surfaces for microbes that may provide new antibiotics to fight antimicrobial resistance and encouraging students to create a scientific report, complete with hand drawn images of what they saw and encountered. Dr Lee Haines (research co-investigator at LSTM) was involved in this activity. Feedback on the event highlighted the effect it had both on audiences and the volunteers involved, see some examples below:

• The ingenuity and excitement about swabbing for bacteria took me off guard. Who likes swabbing for critters? Well this group did, and it ended up being a competition about who could swab the most disgusting place imaginable. In the end, this quest produced something scientifically astounding - a bacterial isolate from an old magnifying glass that was a super-secreter of something antimicrobial. How amazing is that? These kids played a role in a scientific discovery that has the potential to become something life-saving. Without such outreach activities like this, and the enthusiasm of the participants, this discovery would never have happened.

• When kids can interact with real scientists, it does several amazing things. In my case, it helped reverse a gender stereotype that all scientists are old white men. It also uncovers a whole new world, via microscopy, which unleashes the imagination. science engagement also helps people deal with fear. If you can understand and appreciate that which scares you, like bugs, then suddenly the fear is replaced by understanding and sometimes even a bit of wonder. Who knew tsetse and mosquito babies could hold such fascination?!

• i still think of my interaction with one of the young adults helping us organise all the kids.
he was just as amazed with the science as the kids and was synthesizing the information being told him.
so many questions asked. it made me realise we still have such a long way to go to pass on our knowledge to everyone.
after a few minutes of digesting what he had been told about mosquito biology, he asked me if mosquitoes are susceptible to diabetes.
such far out thinking but with logic and reason - if you could get all the sugar feeding male mosquitoes to contract diabetes, then they all would die and would not be able to breed. how's that for a novel vector control strategy? why not?!
why do we always bias our research to target female, blood feeding, mosquitoes? i walked away from this interaction with even more things to ponder as i returned to the lab.

The impact of this activity was engaging an underprivileged community of kids, aged 8 - 17, in scientific discovery. Audience reported change in views as did colleagues who were volunteering. Several colleagues returned to help with other workshops.
Year(s) Of Engagement Activity 2018
URL https://www.lstmed.ac.uk/news-events/events/microbes-to-mosquitoes-workshop-at-centre-63
 
Description School visit (Bristol) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Researcher visited a primary school and talked to children across two classes (30 children each) about topics related to the grant research - maternal investment in insects. Some specimens were brought so children could interact closely with insects, and had the opportunity to ask questions.
Year(s) Of Engagement Activity 2019,2020
 
Description School visit to LSTM as part of the London International Youth Science Forum 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact A group of students visited LSTM as part of the the London International Youth Science Forum (LIYSF), which is a residential event at Imperial and the Royal Geographical Society, which involves "lecture demonstrations from leading scientists, visits to world class laboratories and universities combined with cultural interaction, with 500 students aged 16-21 years old from 70 countries" https://www.liysf.org.uk/. In many of the student feedback comments, they were particularly impressed by the remarkable tsetse life history and reproduction.
Year(s) Of Engagement Activity 2019
 
Description Talk at the Bristol Entomological Research Colloquium during National Insect Week 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact A talk was given by Dr Sinead English during the Bristol Entomological Research Colloquium to explain her current research on viviparity in tsetse flies and cockroaches, and work on why senescence occurs in flies and the implications for understanding the diseases they transmit. The talk sparked questions about the unusual life histories of these animals afterwards, and several postgraduate students approached the speaker later to express interest in understanding more about live-bearing in insects and to visit the breeding colony.
Year(s) Of Engagement Activity 2018
URL http://www.nationalinsectweek.co.uk/events/bristol-entomological-research-colloquium