Leishmania donovani is an obligate intracellular parasite that infects macrophages of the vertebrate host, resulting in
visceral leishmaniasis in humans, which is usually fatal if untreated. The molecular mechanisms involved in host-parasite interaction leading to attachment on the cell surface and subsequent internalization of the parasite are poorly characterized.
Cholesterol is a major constituent of eukaryotic membranes and plays a crucial role in cellular membrane organization, dynamics, function, and sorting. It is often found distributed non-randomly in domains in membranes. Recent observations suggest that
cholesterol exerts many of its actions by maintaining a specialized type of membrane domain, termed "
lipid rafts", in a functional state.
Lipid rafts are enriched in
cholesterol and
sphingolipids, and have been thought to act as platforms through which signal transduction events are coordinated and pathogens gain entry to infect host cells. We report here that
cholesterol depletion from macrophage plasma membranes using
methyl-beta-cyclodextrin (MbetaCD) results in a significant reduction in the extent of leishmanial
infection. Furthermore, the reduction in the ability of the parasite to infect host macrophages can be reversed upon replenishment of cell membrane
cholesterol. Interestingly, these effects were not observed when parasites were serum-opsonized, indicating a specific requirement of
cholesterol to mediate entry via the non-opsonic pathway. Importantly, we show that entry of Escherichia coli remains unaffected by
cholesterol depletion. Our results therefore point to the specific requirement of plasma membrane
cholesterol in efficient attachment and internalization of the parasite to macrophage cells leading to a productive
infection. More importantly, these results are significant in developing novel therapeutic strategies to tackle
leishmaniasis.