The Toll-Like Receptor 2 agonist PEG-Pam2Cys as an immunochemoprophylactic and immunochemotherapeutic against the liver and transmission stages of malaria parasites
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 effec...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-12-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320718300630 |
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doaj-1de92de8ef5d413588a86447479f5274 |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Medard Ernest Carol Hunja Yuka Arakura Yohei Haraga Hussein M. Abkallo Weiguang Zeng David C. Jackson Brendon Chua Richard Culleton |
| spellingShingle |
Medard Ernest Carol Hunja Yuka Arakura Yohei Haraga Hussein M. Abkallo Weiguang Zeng David C. Jackson Brendon Chua Richard Culleton The Toll-Like Receptor 2 agonist PEG-Pam2Cys as an immunochemoprophylactic and immunochemotherapeutic against the liver and transmission stages of malaria parasites International Journal for Parasitology: Drugs and Drug Resistance |
| author_facet |
Medard Ernest Carol Hunja Yuka Arakura Yohei Haraga Hussein M. Abkallo Weiguang Zeng David C. Jackson Brendon Chua Richard Culleton |
| author_sort |
Medard Ernest |
| title |
The Toll-Like Receptor 2 agonist PEG-Pam2Cys as an immunochemoprophylactic and immunochemotherapeutic against the liver and transmission stages of malaria parasites |
| title_short |
The Toll-Like Receptor 2 agonist PEG-Pam2Cys as an immunochemoprophylactic and immunochemotherapeutic against the liver and transmission stages of malaria parasites |
| title_full |
The Toll-Like Receptor 2 agonist PEG-Pam2Cys as an immunochemoprophylactic and immunochemotherapeutic against the liver and transmission stages of malaria parasites |
| title_fullStr |
The Toll-Like Receptor 2 agonist PEG-Pam2Cys as an immunochemoprophylactic and immunochemotherapeutic against the liver and transmission stages of malaria parasites |
| title_full_unstemmed |
The Toll-Like Receptor 2 agonist PEG-Pam2Cys as an immunochemoprophylactic and immunochemotherapeutic against the liver and transmission stages of malaria parasites |
| title_sort |
toll-like receptor 2 agonist peg-pam2cys as an immunochemoprophylactic and immunochemotherapeutic against the liver and transmission stages of malaria parasites |
| publisher |
Elsevier |
| series |
International Journal for Parasitology: Drugs and Drug Resistance |
| issn |
2211-3207 |
| publishDate |
2018-12-01 |
| description |
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. Keywords: Malaria, Plasmodium, Pam2Cys, TLR-2 |
| url |
http://www.sciencedirect.com/science/article/pii/S2211320718300630 |
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doaj-1de92de8ef5d413588a86447479f52742020-11-24T21:43:00ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072018-12-0183451458The Toll-Like Receptor 2 agonist PEG-Pam2Cys as an immunochemoprophylactic and immunochemotherapeutic against the liver and transmission stages of malaria parasitesMedard Ernest0Carol Hunja1Yuka Arakura2Yohei Haraga3Hussein M. Abkallo4Weiguang Zeng5David C. Jackson6Brendon Chua7Richard Culleton8Malaria Unit, Department of Pathology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, JapanMalaria Unit, Department of Pathology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, JapanMalaria Unit, Department of Pathology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, JapanMalaria Unit, Department of Pathology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, JapanMalaria Unit, Department of Pathology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, JapanDepartment of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, 3010, Victoria, AustraliaDepartment of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, 3010, Victoria, Australia; Research Center for Zoonosis Control, Hokkaido University, Sapporo, 001-0020, Japan; Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, 001-0020, JapanDepartment of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, 3010, Victoria, Australia; Research Center for Zoonosis Control, Hokkaido University, Sapporo, 001-0020, Japan; Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, 001-0020, Japan; Corresponding author. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, 3010, Victoria, Australia.Malaria Unit, Department of Pathology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan; Corresponding author. Malaria Unit, Department of Pathology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.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. Keywords: Malaria, Plasmodium, Pam2Cys, TLR-2http://www.sciencedirect.com/science/article/pii/S2211320718300630 |