Host-Parasite Interactions of Intraerythrocytic Malaria Infections

Introduction/Rationale: Malaria infections debilitate communities every year, with the highest fatality rates occurring in children. Plasmodium parasites have complicated host immune evasion tactics that remain poorly understood and contribute to the difficulties in treating this disease. At the asexual replication stage of its life cycle, the parasite is known to regulate the plasma membrane of its host red blood cell (iRBC) to prevent a loss of membrane asymmetry, which would reveal apoptosis signals like phosphatidylserine (PS) and prompt phagocytic clearance via interactions with PS receptors, such as CD36. However, how the parasite maintains membrane asymmetry to evade detection is unknown.

Methods: To study the interaction of iRBCs with host phagocytes we developed a flow cytometry-based assay using the pH-sensitive fluorophore pHrodo. Using this system, we show that CD36-/- macrophages phagocytose iRBCs at a lower rate than wildtype macrophages. Further studies utilizing LysMCreCD36flox mice identified that mice lacking CD36 expression on monocytes and macrophages had significantly higher parasitemia within 4 days of infection. These data suggest that CD36 is critical for early control of malaria infections.

Results: Published data suggest that parasites can transport phospholipids to the iRBC membrane, so we hypothesized that this process may be critical for preserving membrane asymmetry of the iRBC. Given that the apicoplast organelle of Plasmodium parasites is the site of fatty acid synthesis, we employed apicoplast-deficient parasites to investigate if disrupting phospholipid metabolism would result in a loss of membrane asymmetry. We identified that apicoplast-deficient parasites have an increased externalization of PS, supporting the hypothesis that membrane asymmetry is regulated in part by the apicoplast organelle.

Conclusion: Our data suggest that targeting the apicoplast therapeutically could improve the ability of the immune system to clear iRBCs by impairing the immune evasion abilities of the parasite.