The intraerythrocytic cycle of Plasmodium spp. causes all of the pathological features associated with human malaria. The cycle begins with invasion of host erythrocytes by free asexual stage merozoites. The invasion process requires adherence to the erythrocyte surface and a parasite-induced invagination of the erythrocyte plasma membrane. This parasite-induced invagination does not occur via clathrin-mediated endocytosis or other well characterized types of endocytosis and likely involves unidentified parasite-erythrocyte interactions that serve to weaken and disassemble the host cytoskeleton and allow for the extreme membrane deformation observed during the invasion process. Several studies implicate host receptor signaling pathways in plasmodial invasion. Our studies have shown that parasite invasion and intraerythrocytic growth involve host signaling pathways as evidenced by the observations that adrenergic receptor antagonists and Gs inhibition inhibits invasion and growth (Harrison et al, 2003;Murphy et al, in process). The role of Gs signaling in both normal erythrocyte physiology and during plasmodial invasion and maturation is largely unknown. The difficulty in studying host pathways in the context of malaria invasion lies in devising ways to selectively manipulate host pathways without altering parasite processes. We have developed a method to introduce peptides/proteinaceous cargo into erythrocytes such that they continue to support signaling and malaria infection. This gives us an added tool to selectively influence host cell pathways without influencing intraparasitic processes. We hypothesize that the invading plasmodial parasite influences one or more host erythrocyte signaling pathways downstream of Gs. Here, I propose to study erythrocyte Gs effectors in the context of malaria invasion in order to determine the mechanism by which adrenergic receptor and Gs signaling influence malarial invasion. In order to study the role of Gs effectors in malaria infection, I will specifically inhibit host erythrocyte Gs-modulated mechanisms and test the effect of such manipulations in invasion. Knowledge concerning malaria invasion may result in the identification of drug targets and subsequent development of antimalarials, thus leading to reduced human suffering from this devastating parasite.
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|Tamez, Pamela A; Liu, Hui; Fernandez-Pol, Sebastian et al. (2009) Stage-specific susceptibility of human erythroblasts to Plasmodium falciparum malaria infection. Blood 114:3652-5|