Stimulating the host innate immune response to fight the early stages of malaria infection

• Project/Area Number: 16K21233
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Parasitology (including sanitary zoology); Immunology
• Research Institution: Nagasaki University
• Principal Investigator: CULLETON Richard 長崎大学, 熱帯医学研究所, 准教授 (10503782)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: Malaria / Pam2Cys / vaccine / antimalarial drug / malaria

Outline of Final Research Achievements

We investigated 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 S-[2,3-bis(palmitoyloxy)propyl] cysteine (Pam2Cys) against the hepatocytic stages, erythrocytic stages and gametocytes of Plasmodium yoelii was investigated. PEG-Pam2Cys significantly reduces the numbers of malaria parasites in the livers of mice following challenge with sporozoites. We also show that treatment can clear parasites from the liver when administered subsequent to the establishment of infection. PEG-Pam2Cys can reduce the numbers of mosquitoes that are infected 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.

Research Products

• [Journal Article] Schistosoma mansoni infection suppresses the growth of Plasmodium yoelii parasites in the liver and reduces gametocyte infectivity to mosquitoes. (2018)
  • Author(s): Moriyasu, T., Nakamura, R., Deloer, S., Senba, M., Kubo, M., Inoue, M., Culleton, R., Hamano, S.
  • Journal Title: PLoS Negl. Trop. Dis. e0006197. Volume: 12 Issue: 1 Pages: e0006197-e0006197
  • DOI: 10.1371/journal.pntd.0006197
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An assay for the identification of Plasmodium simium infection for diagnosis of zoonotic malaria in the Brazilian Atlantic Forest (2018)
  • Author(s): Alvarenga DA, Culleton R, Pina-Costa Ad, Rodrigues D, Junior CB, Silva S, Nunes AJ, J Souza jr JCd, Hirano Z, Moreira ZB, Pissinatti A, Abreu F, Areas AL, Lourenco-de-Oliveira R, Zalis MG, Brasil P, Ferreira-da-Cruz MdF, Daniel-Ribeiro CT, Alves de Brito CF
  • Journal Title: Scientific Reports Volume: 8 Issue: 1
  • DOI: 10.1038/s41598-017-18216-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Outbreak of human malaria caused by Plasmodium simium in the Atlantic Forest in Rio de Janeiro: a molecular epidemiological investigation (2017)
  • Author(s): Brasil P, Zalis M G, de Pina-Costa A, Siqueira AM, Bianco Junior C, Silva S, Areas ALL, Pelajo-Machado M, de Alvarenga DAM, Santelli ACFdS, Albuquerque HG, Cravo P, de Abreu FVS, Peterka CL, Zanini GM, Suarez-Mutis MC, Pissinatti A, Lourenco-de-Oliveira R, Brito CFAd, Ferreira-da-Cruz MdF, Culleton R, Daniel-Ribeiro CT
  • Journal Title: The Lancet Global Health Volume: 5 Issue: 10 Pages: e1038-e1046
  • DOI: 10.1016/s2214-109x(17)30333-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Return of chloroquine sensitivity to Africa? Surveillance of African Plasmodium falciparum chloroquine resistance through malaria imported to China (2017)
  • Author(s): Lu F、Zhang M、Culleton RL、Xu S、Tang J、Zhou H、Zhu G、Gu Y、Zhang C、Liu Y、Wang W、Cao Y、Li J、He X、Cao J、Gao Q
  • Journal Title: Parasites & Vectors Volume: 10 Issue: 1 Pages: 355-355
  • DOI: 10.1186/s13071-017-2298-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Artemisinin-Resistant Plasmodium falciparum in Africa (2017)
  • Author(s): Lu F, Culleton R, Cao J
  • Journal Title: New England Journal of Medicine Volume: 377 Issue: 3 Pages: 305-306
  • DOI: 10.1056/nejmc1705789
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rapid identification of genes controlling virulence and immunity in malaria parasites (2017)
  • Author(s): Abkallo HM, Martinelli A, Inoue M, Ramaprasad A, Xangsayarath P, Gitaka J, Tang J, Yahata K, Zoungrana A, Mitaka H, Acharjee A, Datta PP, Hunt P, Carter R, Kaneko O, Mustonen V, Illingworth CJR, Pain A, Culleton R
  • Journal Title: PLOS Pathogens Volume: 13 Issue: 7 Pages: e1006447-e1006447
  • DOI: 10.1371/journal.ppat.1006447
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Detection of the Plasmodium falciparum Kelch-13 gene P553L mutation in sporozoites isolated from mosquito salivary glands in South-Central Vietnam (2017)
  • Author(s): Maeno Y, Quang NT, Culleton R, Kawai S, Masuda G, Hori K, Nakazawa S, Marchand RP
  • Journal Title: Parasit Vectors Volume: 10(1) Issue: 1 Pages: 308-308
  • DOI: 10.1186/s13071-017-2247-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Emergence of Indigenous Artemisinin Resistant Plasmodium falciparum in Africa (2017)
  • Author(s): Lu F, Culleton R, Zhang M, Ramaprasad A, von Seidlein L, Zhou H, Zhu G, Tang J, Liu Y, Wang W, Cao Y, Xu S, Gu Y, Li J, Zhang C, Gao Q, Menard D, Pain A, Yang H, Zhang Q & Cao J.
  • Journal Title: New England Journal of Medicine Volume: 376 Issue: 10 Pages: 991-993
  • DOI: 10.1056/nejmc1612765
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Plasmodium knowlesi and human malaria parasites in Khan Phu, Vietnam: Gametocyte production in humans and frequent co-infection of mosquitoes. (2017)
  • Author(s): Maeno Y, Culleton R, Quang NT, Kawai S, Marchand RP, NakazawaS
  • Journal Title: Parasitology Volume: 144 Issue: 4 Pages: 527-535
  • DOI: 10.1017/s0031182016002110
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-human Primate Malaria Parasites: Out of the forest and into the laboratory (2017)
  • Author(s): Martinelli A & Culleton R
  • Journal Title: Parasitology International Volume: 印刷中 Issue: 1 Pages: 55-55
  • DOI: 10.1017/s0031182016002213
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Genetic Diversity And Population Structure Of Plasmodium Falciparum In Lake Victoria Islands, A Region Of Intense Transmission (2016)
  • Author(s): Mulenge FM, Hunja CW, Magiri E, Culleton R, Kaneko A, Aman RA
  • Journal Title: American Journal of Tropical Medicine & Hygiene Volume: 95 Issue: 5 Pages: 1077-1085
  • DOI: 10.4269/ajtmh.16-0383
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome-scale comparison of expanded gene families in Plasmodium ovale wallikeri and Plasmodium ovale curtisi with Plasmodium malariae and with other Plasmodium species. (2016)
  • Author(s): Ansari HA, Templeton JT, Subudhi AK, Ramaprasad A, Tang J, Lu J, Naeem R, Oguike MC, Benavente ED, Clark TG, Sutherland CJ, Barnwell JW, Culleton R＊, Cao J＊ and Pain A＊
  • Journal Title: International Journal for Parasitology Volume: 7519 Issue: 11 Pages: 30135-30137
  • DOI: 10.1016/j.ijpara.2016.05.009
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Little Polymorphism at the K13 Propeller Locus in Worldwide Plasmodium falciparum Populations Prior to the Introduction of Artemisinin Combination Therapies (2016)
  • Author(s): Mita T, Culleton R, Takahashi N, Nakamura M, Tsukahara T, Hunja CW, Zayar ZW, Hitake WW, Marma AS, Dysoley L, Ndounga M, Dzodzomenyo M, Akhwale WS, Kobayashi J, Uemura H, Kaneko A, Hombhanje F, Ferreira MU, Björkman A, Endo H, Ohashi J
  • Journal Title: Antimicrobial Agents and Chemotherapy Volume: 印刷中 Issue: 6 Pages: 3340-3347
  • DOI: 10.1128/aac.02370-15
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Genetic analysis of Plasmodium malariae and Plasmodium ovale from asymptomatic adolescents in South-East Nigeria (2017)
  • Author(s): Richard Culleton
  • Organizer: 第86回日本寄生虫学会
  • Place of Presentation: 北海道大学学術交流会館（北海道・札幌市）
  • Year and Date: 2017-05-28
• [Presentation] Genetic analysis of Plasmodium malariae and Plasmodium ovale from asymptomatic adolescents in South-East Nigeria (2017)
  • Author(s): Richard Culleton
  • Organizer: 13th Nagasaki - Singapore Medical Symposium / Leading Program International Symposium 2017
  • Place of Presentation: 長崎大学坂本キャンパス（長崎県・長崎市）
  • Year and Date: 2017-05-18
• [Presentation] Malaria: A Deadly Zoonosis (2017)
  • Author(s): Richard Culleton
  • Organizer: Japan-Brazil Malaria Research Workshop - fostering new partnership
  • Place of Presentation: サンパウロ（ブラジル）
  • Year and Date: 2017-03-15
  • Int'l Joint Research
• [Presentation] Phenotypic, Genotypic, and Transcriptomic Characterisation of the Plasmodium vinckei clade of Rodent Malaria Parasites (2017)
  • Author(s): Richard Culleton
  • Organizer: 第１６回あわじしま感染症・免疫フォーラム
• [Presentation] Genetic Analysis of Drug Resistance Genes in Plasmodium falciparum, Plasmodium malariae andPlasmodium ovale Isolated from Asymptomatic individuals in South-East Nigeria (2017)
  • Author(s): Ernest Medard（研究協力者）
  • Organizer: 第16回あわじしま感染症・免疫フォーラム
• [Presentation] Genome-scale comparison of expanded gene families in Plasmodium ovale wallikeri and Plasmodium ovale curtisi with Plasmodium malariae and with other Plasmodium species (2016)
  • Author(s): Richard Culleton
  • Organizer: 第１５回あわじしま感染症・免疫フォーラム
  • Place of Presentation: 淡路夢舞台国際会議場（兵庫県・淡路市）
  • Year and Date: 2016-09-06
• [Presentation] Trans-generational effects of rearing temperature on susceptibility of mosquitoes to infection with malaria parasites. (2016)
  • Author(s): Ernest Medard
  • Organizer: 第１５回あわじしま感染症・免疫フォーラム
  • Place of Presentation: 淡路夢舞台国際会議場（兵庫県・淡路市）
  • Year and Date: 2016-09-06
• [Presentation] Pam2Cys as a novel immunochemoprophylactic and immunochemotherapeutic in malaria (2016)
  • Author(s): Richard Culleton
  • Organizer: Zoonoses The 4th Meeting of the Consortium for the Control of Zoonoses
  • Place of Presentation: 北海道大学人獣共通感染症リサーチセンター（北海道・札幌市）
  • Year and Date: 2016-07-07
• [Presentation] Trans-generational effects of rearing temperature on susceptibility of mosquitoes to infection with malaria parasites. (2016)
  • Author(s): Ernest Medard
  • Organizer: The 3rd International Symposium for the Promotion of Science and Technology Innovation Cooporation between Africa and Japan ～Life Innovation and Green Innovation～
  • Place of Presentation: JICA市ヶ谷（東京都・新宿区）
  • Int'l Joint Research