This research will be done primarily in Rio de Janeiro, RJ, Brazil at the National Institute of Cancer in collaboration with Maria Elisabete Costa Moreira as an extension of NIH grant #R01 GM61031. The rationale for this FIRCA grant comes the demonstration that Leishmania amazonensis may be able to subvert the evolutionarily conserved mechanisms for recognizing and removing apoptotic cells in order to penetrate and parasitize mammalian host macrophages - in particular, amastigote expression of phosphatidylserine (PS) and its potential mediation of uptake into macrophages through the phosphatidylserine receptor (PSR) that is involved in apoptotic cell removal and its consequences. Experiments will be conducted to explore the mechanisms by which PS is exposed on the Leishmania surface (from endogenous or exogenous sources), differences between amastigotes and metacyclic (infectious) promastigotes, and variations in PS exposure, distribution and effect among different species of Leishmania. The role of PS and the PS receptor, along with other innate immune system recognition molecules (e.g. the collectin family) that are also involved in apoptotic cell removal will be examined for their role in Leishmania ingestion/infection. In addition, we hypothesize that a unique uptake process, related to, but separable from, macropinocytosis is involved in Leishmania penetration of mammalian host cells. By appropriate use of approaches already worked out for apoptotic cell removal, the possible utilization of these for Leishmania parasitism will be explored. In the third specific aim, use of in vivo manipulation and specific knockout mice will allow extension of the studies of uptake mechanism and infection into mice. Recognition of apoptotic cells induces an active anti-inflammatory and anti-immunogenic effect in vitro and in vivo. Therefore, an expected consequence of Leishmania utilization of similar mechanisms is a comparable effect on inflammatory responses. This may serve to enhance, and its appropriate manipulation to suppress, the infection. ? ?
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