Why does Drosophila vary in susceptibility to parasitoid wasps?

The aim of this grant is to understand why individuals within populations vary in their susceptibility to infection. This variation determines the burden of disease and allows populations to evolve resistance. For reseatchers, it can provide insights into host-parasite coevolution and functioning of immune systems. We will begin by using high-throughput genome sequencing to identify the genetic variants that make the fruit fly Drosophila melanogaster resistant to its most important natural enemy, parasitoid wasps. These results will be verified by generating genetically identical flies that only differ in the variants in question.

We will next identify how these genes make individuals resistant. Hemocytes (blood cells) are the immune cells responsible for killing the parasitoid egg. In resistant flies we have found that hemocytes have moved from sessile clusters associated with neurons into circulation. Furthermore, in our preliminary data we have found a polymorphism in a gene called slit that is strongly associated with resistance. Slit is secreted by neurons and controls cell migration. We will test the hypothesis that resistance is caused by the expression of Slit changing in peripheral neurons so that hemocytes leave sessile clusters and move into circulation, resulting in a constitutively activated immune system that can rapidly kill invading parasitoids.

Genetic variation in susceptibility to infection is often thought to be maintained in populations because resistant alleles are costly, but the causes of these costs are poorly understood. We will examine whether costs result from collateral damage caused by a constitutively activated immune system. Flies that are resistant to parasitoids suffer a marked reduction in fitness, and we will use flies that are genetically identical apart from the variants controlling resistance to identify which resistance genes are costly. To test whether it is cellular immune defences that are costly, we can use genetic tools to remove the hemocytes from these flies and examine whether this removes the costs. To test whether it is the release of hemocytes into circulation that is costly, we will use genetic techniques to return the hemocytes of resistant flies to sessile clusters and release the hemocytes of susceptible flies into circulation, and then measure the effect on fitness.

Genetic resistance is sometimes effective against a broad range of parasites, but is often highly specific. This specificity is surprising in organisms like insects, as mechanistic studies have found that their innate immune system has limited discriminatory power. To resolve this paradox we will test the hypothesis that genes that alter the magnitude of the innate immune response provide broad-spectrum resistance, while genes that overcome parasite factors sabotaging immunity provide specific resistance. Resistance to parasitoids involves both broad-spectrum and specific resistance genes. By tracking genotype frequencies as populations evolve resistance in the lab, we will identify these genes and confirm the results using genetically engineering flies that are identical except for the variants in question. These flies will allow us to test our prediction that broad-spectrum resistance results from an increase in the magnitude of the innate immune response (number of circulating hemocytes), while specific resistance depends on the susceptibility of hemocytes to wasp venoms that disable the immune system.

The primary aim of this grant is to contribute to our fundamental understanding of evolutionary biology and immunology. We will use techniques and theoretical frameworks from very different fields, ranging from ecology to developmental biology. Hence, on the long term, our results will certainly impact the work of applied researchers in these areas. This will, in turn, impact distinct areas such as health and environment. Moreover, our research is a striking way to engage the public to think about evolutionary concepts and their importance for everyday life.

Parasitoids and biological control

Parasitoid wasps are widely used in agriculture to control insect pests, and the evolution of host resistance could cause these programs to fail. Understanding the mechanisms by which hosts evolve resistance will inform efforts to prevent this from happening. For example, if resistance is costly, then resistance evolution can be avoided by strategies that maximise those costs while minimising the strength of selection for resistance. Pattern of cross resistance could be exploited by rotating the use of parasitoids. The rational design of such strategies requires an understanding of cross-resistance and the costs of resistance.


Hematopoiesis and non-communicable disease

Disorders in hematopoiesis cause a wide variety of non-communicable diseases, including leukaemia and various forms of anaemia, and Drosophila is an important model of this process. Our work will contribute to this medically important field in two ways. First, we will identify novel processes leading to the dysregulation of hematopoiesis related with nervous system. Second, we will demonstrate the evolutionary origins of disorders in hematopoiesis, by illustrating that harmful homing of blood cells may evolve because of selection by infectious diseases.

Insect vectors of infectious disease

Genetic variation in the immune response of insect vectors of human and animal disease determines the rate at which disease transmission occurs and therefore the burden of disease in humans and farm animals. In recent years there has been considerable effort into manipulating natural mosquito populations to increase resistance. For example, when a bacterial symbiont was found to make Drosophila resistant to viral infection, it was transferred into the mosquito Aedes aegypti, and is now being released on a large scale to block dengue transmission.

Our work will identify how insects evolve resistance to infection, and these processes can be targeted in mosquitoes. For example, transgenes could be driven through populations to mimic the phenotype we are studying to prevent parasite transmission. A fundamental understanding of how resistance evolves will allow transgenes to be designed that maximise resistance and reduce costs.



Delivering and training highly skilled researchers

With this project there will be many opportunities for a postdoc to develop skills in the generation and quantitative analysis of large genomic datasets, and in the analysis of insect immunity. The Jiggins lab is an excellent environment to learn these skills.

Public understanding of science

The determinants of disease susceptibility is an easily accessible topic to the public - people care what determines why they might get ill, or why a mosquito might transmit a disease. This makes it an excellent tool with which to engage the public, and make the case that evolution can affect their lives. Information on our research will be disseminated at public engagement events such as the Cambridge Science Festival, and events that are aimed at sixth formers who might apply to Cambridge. In the 'Pathways to impact' we propose a citizen science project. These approaches will allow us to talk with the public and communicate scientific concepts. We will also publicise our work to the public through the university press office and make our website accessible to the public.