Every year, 2 million people are infected with leishmaniasis from sandfly bites, and over 60,000 die from the visceral form that attacks internal organs. The problem is that scientists do not fully understand why some people develop mild skin ulcers while others get a fatal infection, or how the immune system’s response to the parasite can sometimes damage the spleen, liver, and bone marrow. Current experimental models in mice are useful but incomplete—they may miss key differences in how humans actually fight the parasite. This research will study human and mouse tissues side by side, using new microscopy techniques to watch how white blood cells called phagocytes engulf Leishmania in the liver and how gene expression changes during infection. By examining tissue samples from patients during treatment and after death, the team can directly compare human immune responses with those in mice. If successful, this work will improve the predictive value of animal models for testing drugs and vaccines, potentially reducing the number of animals needed in future experiments while accelerating the development of treatments for a disease that kills tens of thousands annually.
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Leishmaniasis is a disease caused when people are bitten by sandflies that contain a small single cell parasite, called Leishmania. Although some people never get sick, many develop local skin ulcers or a potentially fatal disease that affects the internal organs, called visceral leishmaniasis (kala azar or ?black sickness?). Why different people get different types of disease is not known, but it may relate to the type of Leishmania they are infected with and their health of their immune system. 2 million people get leishmaniasis every year (in 88 countries, including some in Europe) and visceral leishmaniasis is responsible for over 60,000 deaths annually. As the parasites live deep in the tissues (spleen, liver, bone marrow), it is difficult in sick people to see exactly how they are affecting our immune system and to find ways to improve how the immune system deals with them. Therefore, we need to use experimental models of the disease to study these questions. Although much progress has been made, experimental models cannot provide the whole picture and there may be important differences in how mice and people respond to these parasites, or in how much damage the immune system does to our organs trying to fight the infection. We wish to conduct an integrated research programme to let us study disease processes in human and mouse tissues side by side. This approach is important, both to see whether the responses in mice also occur in man (thus supporting clinical study of drugs/vaccines developed in mice) and conversely to see whether we can improve the predictive nature of models used for testing drugs/vaccines. We will be studying how Leishmania is eaten by white blood cells (phagocytes) in the liver, and how the expression of our genes changes in response to the infection. We will develop new microscopy approaches that allow us to see how infection affects phagocyte function and their ability to coordinate inflammation. We will use tissues samples taken from people during treatment and also at post mortem, to observe how well their immune systems have responded to treatment or to understand what went wrong that led to their death. In combination, these studies will provide much important new information on human disease, and help to reduce and improve the quality of animal experimentation.
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