The eosinophil: Anti-parasite effector cell or mediator of pathology?

Parasites can live relatively quietly in their hosts or they can cause excessive tissue damage which seriously affects the life of the infected individual. This project will study a particular cell type, the eosinophil, which appears to be capable of either curing the individual of disease or of causing harmful tissue reactions. Millions of people and animals in the world are infected by parasitic nematode worms. These parasites occupy a multitude of different sites within the body, from the gut to the skin or blood. The damage that worms cause varies between different parasite species and also between different infected individuals. Some individuals are relatively resistant to infection with worms, while others, are particularly susceptible. Resistance to parasitic nematode disease depends on the immune responses that the body develops to fight these infections. Interestingly, in many infections, although a specific type of immune response can kill parasitic worms, that particular immune response may also be guilty of damaging the tissues of the host organism. Therefore in areas of the world where individuals are continually at risk of infection with parasitic worms, the immune response can be viewed as a finely/balanced see-saw that rocks between the ability to kill parasites and the ability of the response to cause harm. As researchers, we wish to find out the triggers that push the see-saw in one direction or the other and the controls that the body puts in place to prevent the balance from being biased too strongly in one or other direction. We have identified a particular cell-type, the eosinophil, that appears to be important in parasite-killing but when over-active it is also involved in tissue damage. Our aim in this research is to definitively establish, once and for all, that this cell type, the eosinophil, is capable of killing parasites and of damaging tissues. We will then establish the biological factors that are produced by eosinophils in both of these situations to try and define whether there are differences between esoinophils that kill parasites and those that cause damage. Lastly we will try to identify particular immune responses that limit the damage caused by eosinophils. This work is particularly exciting because it is only recently that scientists have developed the technological tools that will help us to identify the role played by eosinophils. In addition, immune responses to parasitic worms are remarkably similar to the immune responses that cause asthma, therefore the results of our studies will be useful both for fighting infections with worms and for fighting the symptoms of asthma.

Eosinophilia is associated both with asthmatic disease and with parasitic helminth infection. However, for many years the function of eosinophils in pathology and/or protection against parasites has been contentious. Recently, the generation of mice that specifically lack eosinophils means that the exact role of eosinophils in both protection and the development of pathology during helminth infection can be pinpointed. Indeed, in the asthma field there is now renewed interest in this cell type, because using these mice, eosinophils have been shown to play an integral role in the development of pathology. We will use a well-established mouse model of filarial infection, in which parasite survival is easily measured and the nematodes induce asthma/like pathology, in order to investigate eosinophil function. Using mice that are solely deficient in eosinophils, we will definitively establish the requirement for eosinophils in protection against a tissue-dwelling parasitic nematode. Concurrently, we will pinpont the importance of eosinophils in the parasite-induced asthmatic-like symptoms that are associated with immunisation followed by challenge nematode infection. We will identify factors upregulated in eosinophils that are involved in pathology and using mice deficient in particular granule proteins we will establish whether the release of distinct secondary granule proteins causes pathology. Lastly we will investigate whether eosinophils are subject to down-modulation by regulatory cells which may act to limit pathology. This work is particularly exciting because it is only recently that several new technological tools have become available that will aid in the success of the study. For example, mice with a bi-cistronic IL-4 knock-in gene linked with green fluoresecent protein (4get mice) allow considerably simplified isolation and recognition of this relatively rare cell type and mice are also available that have large numbers of normal non-activated eosinophils due to overexpression of IL-5 on T cells alone. Consequently, this a pertinent time to ascertain the importance of eosinophils as both effector cell and mediator of immunity in helminth infection. As immunopathology caused by parasitic worms is remarkably similar to asthma-associated pathology, the results of our studies will therefore be informative for therapeutic intervention in both diseases.