Immunopathology and the regulation of immune responses during Leishmania donovani infection

Single celled parasites, called Leishmania, can be transmitted to humans by biting sand flies and cause a spectrum of diseases collectively known as leishmaniasis. Leishmaniasis is found in 88 countries and some 15M people are infected at any given time. One form of the disease, in which internal organs are affected (visceral leishmaniasis), accounts for approx 100,000 deaths annually, mainly in children. Visceral leishmaniasis occurs predominantly in India, Bangladesh, Nepal, The Sudan and Brazil, but it also occurs in many countries bordering the Mediterranean. The spread of HIV makes visceral leishmaniasis an increasingly important infection. Visceral leishmaniasis is also a severe disease of dogs, with 2-3M dogs infected in Europe alone. Infected dogs help maintain transmission of the disease to man. To understand why people die from this infection, and to help develop new vaccines and drugs for human and veterinary use, it is essential to understand more about how the infection attacks our organs and undermines the immune responses that normally protect us from infection. By studying the nature of the disease in experimental models and how it affects immunity, we shall be able to suggest novel approaches to treatment and aid in effective vaccine design. In addition to publication in peer-reviewed public access journals, the results from this study will be communicated via Outreach activities and by active public relations to disseminate news of important breakthroughs via the local and national press.

Visceral leishmaniasis (VL) is a major public health problem in developing countries and there is urgent need to develop new therapeutic approaches to combat active infection and control parasite persistence. Many of the features of human VL can be observed in murine models and experimental VL also provides, in more general terms, a excellent model for studying immune regulation. Notably, the outcome of infection is organ-specific and immune responses are intimately linked to local pathology. Whilst a variety of regulatory pathways have been proposed to control the outcome of infectious disease, these have been poorly characterised to date in VL, and the basis of the regulatory events that lead to chronic infection and parasite persistence represents a major gap in our knowledge. In this proposal, we aim to extend our understanding of immune regulation in experimental VL, building on i) the discovery of a novel pathway by which tissue stromal cells directly regulate the differentiation of dendritic cells with constitutive regulatory function, and ii) the identification of functional and temporal heterogeneity in dendritic cell populations obtained from infected mice. We will make a molecular analysis of stromal cells to identify how they regulate dendritic cell differentiation and to generate novel tools to analyse and manipulate this pathway in vitro and in vivo. We will also make a comprehensive study of the function of regulatory DC and T cells in disease, employing state-of-the-art approaches in cellular immunology (including the use of real time in vivo imaging). Together, these studies will provide essential data on the host response to VL, informing the development of new therapeutics, and provide novel basic information on immunoregulation during parasitic disease.