マラリア原虫の肝臓期と伝播期に対する Toll様受容体2のアゴニストPEG-Pam2Cysを用いた免疫化学予防と免疫化学療法

Both vaccine and therapeutic approaches to malaria are based on conventional paradigms; whole organism or single antigen epitope-based vaccines administered with or without an adjuvant, and chemotherapeutics (anti-malaria drugs) that are toxic to the parasite. Two major problems that limit the effectiveness of these approaches are i) high levels of antigenic variation within parasite populations rendering vaccination efficacy against all variants difficult, and ii) the capacity of the parasite to quickly evolve resistance to drugs. We describe a new approach to both protection from and treatment of malaria parasites that involves the direct stimulation of the host innate immune response through the administration of a Toll-Like Receptor-2 (TLR2) agonist. The activity of PEG-Pam2Cys against the hepatocytic stages, erythrocytic stages and gametocytes of the rodent malaria parasite Plasmodium yoelii was investigated in laboratory mice. We show that administration of PEG-Pam2Cys, a soluble form of the TLR2 agonist S-[2,3-bis(palmitoyloxy)propyl] cysteine (Pam2Cys), significantly and dramatically reduces the numbers of malaria parasites that grow in the livers of mice following subsequent challenge with sporozoites. We also show that treatment can also clear parasites from the liver when administered subsequent to the establishment of infection. Finally, PEG-Pam2Cys can reduce the numbers of mosquitoes that are infected, and the intensity of their infection, following blood feeding on gametocytaemic mice. These results suggest that this compound could represent a novel liver stage anti-malarial that can be used both for the clearance of parasites following exposure and for the prevention of the establishment of infection.長崎大学学位論文 学位記番号:博(医歯薬)甲第1173号 学位授与年月日:令和元年9月20日Author: Medard Ernest, Carol Hunja, Yuka Arakura, Yohei Haraga, Hussein M. Abkallo, Weiguang Zeng, David C. Jackson, Brendon Chua, Richard CulletonCitation: International Journal for Parasitology: Drugs and Drug Resistance, 8(3), pp.451-458; 2018Nagasaki University (長崎大学)課程博