Sunday, May 18, 2025
5/18/2025
Plasmodium and Anopheles midgut interactive proteins influence malaria transmission - SUMMARY Malaria caused by Plasmodium parasites affects millions of people worldwide. The life cycle of the malaria parasites involves a vertebrate host and mosquito vector. Transmission through Anopheles mosquitoes is an obligatory step of the parasite’s life cycle and represents a vulnerable target for transmission-blocking strategies. After the ingestion of Plasmodium-infected blood, the parasites inside the mosquito’s midgut undergo gametogenesis and fertilization, and the resultant zygote transforms into a motile ookinete. Within about 24 hours, the ookinete must escape the blood bolus, penetrate the midgut peritrophic matrix and epithelium, and eventually lie beneath the basal lamina for sporogonic development. Despite the significance of midgut invasion for the successful transmission of the parasite, the molecular mechanisms of the invasion process are poorly understood. We hypothesize that the parasite-mosquito midgut interactive proteins serve essential roles in parasite invasion in mosquitoes and that disrupting these interactions will stop malaria transmission. To better understand the parasite invasion process in the midgut, we have performed large-scale screening of a midgut protein library and a parasite sexual-stage protein library and identified candidate proteins from each library that potentially mediate the parasite-midgut interactions. Based on these discoveries, this proposed research will study the molecular mechanisms of parasite-midgut interactions and evaluate these protein candidates as novel targets for transmission-blocking vaccines. We will functionally characterize these mosquito and parasite proteins to study their tissue distribution and subcellular localization and identify their binding partners. We will also determine their transmission-blocking potential using in vitro mosquito feeding assays and map the essential epitopes using a panel of monoclonal antibodies. Finally, we will design chimeric antigens that target both the parasite and mosquito antigens to achieve stronger transmission-blocking activities. The long-term goal of this project is to gain a significant understanding of the mechanisms of parasite-mosquito midgut interactions and develop new approaches to stop malaria transmission.
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