The role of neutrophil granulocytes as target cells and transport vehicle for intracellular pathogens

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Neutrophil granulocytes (PMN) are recruited rapidly to the skin infected with Leishmania major (L. major) and PMN have been recently shown to facilitate the development of leishmanial disease. We have found that PMN are able to phagocytose Leishmania promastigotes both in vitro and in vivo. Importantly, the parasites delay the spontaneous apoptosis of infected PMN for at least 24-72 h and, as a result, parasites survive intracellularly in PMN. These data suggested that the invasion of PMN is an important early step to establish the leishmanial infection. The aim of the proposed study is to understand the role of PMN in the disease development after infection with intracellular pathogens. The study will investigate the molecular basis of recognition of Leishmania by PMN and the mechanism of pathogeninduced inhibition of PMN apoptosis. Once the anti-apoptotic pathway used by Leishmania is clarified, it will tested whether this is a general mechanism of intracellular pathogens to inhibit PMN apoptosis. In these experiments Chlamydia pneumoniae will be used, a bacterium which we have shown to inhibit PMN apoptosis as well. Experiments are planned to analyse the role of PMN as transport vehicle of Leishmania and Chlamydia contributing to the "silent entry" of the pathogens into monocytes/ macrophages. In order to understand the molecular mechanisms of PMN function in an infection, cDNA microarray analysis will be carried out to identify genes expressed by neutrophils after exposure to intracellular pathogens.