Differences in human macrophage receptor usage, lysosomal fusion kinetics and survival between logarithmic and metacyclic Leishmania infantum chagasi promastigotes.
Cell Microbiol. 2009 Dec; 11(12):1827-41
This manuscript demonstrates that Leishmania life cycle stages utilize different human macrophage receptors for entry, resulting in divergent intracellular fates. These results also provide an explanation for discordant reports regarding receptor utilization by Leishmania.
This study assessed the differences between how virulent metacyclic Leishmania infantam chagasi (Lic) promastigotes and avirulent Lic logarithmic promastigotes are phagocytosed by human monocyte-derived macrophages. While both stages co-localized with complement receptor 3 (CR3), only logarithmic promastigotes engaged mannose receptor (MR). Following entry, logarithmic promastigote-containing vacuoles accumulated lysosome-associated membrane protein-1 (LAMP-1) early following phagocytosis, whereas vacuoles containing metacyclic promastigotes exhibited a delay in LAMP-1 accumulation. While this study puts forth an interesting hypothesis to account for intracellular survival differences between the two life cycle stages, the role that CR3 and MR play in influencing endocytic trafficking of Leishmania parasites remains to be completely elucidated.
McDowell M: F1000Prime Recommendation of [Ueno N et al., Cell Microbiol 2009, 11(12):1827-41]. In F1000Prime, 05 Feb 2010; DOI: 10.3410/f.1797994.1327100. F1000Prime.com/1797994#eval1327100
F1000Prime Recommendations, Dissents and Comments for [Ueno N et al., Cell Microbiol 2009, 11(12):1827-41]. In F1000Prime, 06 Dec 2013; F1000Prime.com/1797994
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The obligate intracellular protozoan, Leishmania infantum chagasi (Lic) undergoes receptor-mediated phagocytosis by macrophages followed by a transient delay in phagolysosome maturation. We found differences in the pathway through which virulent Lic metacyclic promastigotes or avirulent logarithmic promastigotes are phagocytosed by human monocyte-derived macrophages (MDMs). Both logarithmic and metacyclic promastigotes entered MDMs through a compartment lined by the third complement receptor (CR3). In contrast, many logarithmic promastigotes entered through vacuoles lined by mannose receptors (MR) whereas most metacyclic promastigotes did not (P < 0.005). CR3-positive vacuoles containing metacyclic promastigotes stained for caveolin-1 protein, suggesting CR3 localizes in caveolae during phagocytosis. Following entry, the kinetics of phagolysosomal maturation and intracellular survival also differed. Vacuoles containing metacyclic parasites did not accumulate lysosome-associated membrane protein-1 (LAMP-1) at early times after phagocytosis, whereas vacuoles with logarithmic promastigotes did. MDMs phagocytosed greater numbers of logarithmic than metacyclic promastigotes, yet metacyclics ultimately replicated intracellularly with greater efficiency. These data suggest that virulent metacyclic Leishmania promastigotes fail to ligate macrophage MR, and enter through a path that ultimately enhances intracellular survival. The relatively quiescent entry of virulent Leishmania spp. into macrophages may be accounted for by the ability of metacyclic promastigotes to selectively bypass deleterious entry pathways.
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