Interaction between Leishmania parasites and mammalian macrophages

Leishmania parasites are digenetic protozoans which infect human hosts and are causative agents of a series of diseases known under the name of leishmaniasis. Macrophages represent the main host. Hence the interaction between Leishmania and macrophages is a fundamental step in the development of the disease. Many studies have been undertaken to understand early stages of the parasite interaction with macrophages; however, few have investigated the later stages of infection. This study was undertaken to develop an experimental model to examine the fate of the parasites when they leave the safe environment represented by their host macrophage. Primarily, the study investigated how Leishmania spread to neighbouring cells without being recognized and killed by the immune system defences. Three Old World species of Leishmania parasites: L. aethiopica, L. major and L. tropica, all responsible for the cutaneous form of the disease, were used. A model of infection was described using two cell lines well known for supporting infection: THP-1 and U937. Axenic amastogotes for L. aethiopica parasites were obtained and used to identify drugs active against the infection. On the basis of the information available in the literature, a model was suggested involving interaction of intracellular parasites with the host cells’ apoptotic machinery. Specifically it was suggested that Leishmania parasites were able to induce incomplete activation of apoptosis in the host cells. This hypothesis was confirmed by the findings that during infection an increased number of host cells showed two features associated with early apoptosis but not the one associated with the later stage. Results were validated in peripheral blood derived human macrophages. The information obtained from comparative proteomics analysis of the infection confirmed that Leishmania regulates apoptotic processes. On the basis of the results obtained a model was presented to explain how induction of apoptosis allows intracellular amastigotes to spread unrecognised to uninfected macrophages without inducing an inflammatory response or losing the host cell’s protection.EThOS - Electronic Theses Online ServiceGBUnited Kingdo