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 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 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 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 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