The role of parasitic phosphatidylserine in the infection of human polymophonuclear neutrophil granulocytes (PMN) by Leishmania major

• Applicant: Professor Dr. Ger van Zandbergen
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2005 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 21110843

The obligate intracellular pathogen Leishmania major (L. major) uses phagocytes as host cells. To establish a productive infection phagocyte defenses are inactivated. For multiplication the parasite uses its final host cell, the macrophage. However, before reaching its final destination L. major first recruits and infects polymorphonuclear neutrophil granulocytes (PMN). Infected apoptotic PMN are then used by the parasite as transport vehicle to enter macrophages. Consequently, PMN defenses have to be inactivated first to enable parasite survival. The best example of a non inflammatory entry into phagocytes is the uptake of apoptotic cells. Immune responses are suppressed by the recognition of phosphatidyl serine (PS) expressed on the outer membrane of apoptotic cells. We found that infective promastigotes populations taken either from in vitro cultures or from the sand fly vector contain apoptotic PS-positive parasites. In vivo, in a cutaneous infection model susceptible BALB/c mice infected with purified PS-negative parasites did not develop disease. Disease development depended on the presence of PS-positive parasites. These data suggest that PS is a key mediator in disease development. In vitro, PS-positive parasites enable survival of PS-negative parasites in PMN by a still unknown mechanism. In this project, our main objective will be to elucidate the mechanism of PS-mediated suppression of PMN activation. We will compare PS expression on promastigotes with apoptotic cells. We will study the molecules involved in both PS-dependent and PS-independent uptake of parasites by PMN. In the absence or presence of PS-positive parasites, we will assess PMN immune responses towards viable PS-negative parasites. Finally we will generate a mutant parasite strain unable to express PS. Our investigations will help to understand the pathophysiological mechanisms of Leishmania infections and may provide the base for new therapeutic strategies

• DFG Programme: Research Grants