Epidemiological consequences of reproductive senescence in a long-lived vector

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.

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.

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.