Innate immune regulation by malaria parasites

• Project/Area Number: 20790324
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Parasitology (including Sanitary zoology)
• Research Institution: Osaka University
• Principal Investigator: ジェヴァイア チョバン Osaka University, 免疫学フロンティア研究センター, 特任准教授 (00397712)
• Co-Investigator(Renkei-kenkyūsha): 審良 静男 大阪大学, 免疫学フロンティア研究センター拠点長, 教授 ; 堀井 俊宏 大阪大学, 微生物病研究所分子原虫学分野, 教授 ; 武下 文彦 横浜市立大学, 微生物学(旧細菌学)・分子生体防御学, 客員教授 ; 小山 正平 大阪大学, 免疫学フロンティア研究センターワクチン学, 助教 ; 川越 龍方 大阪大学, 免疫学フロンティア研究センターワクチン学, 助教
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2009: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2008: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 原虫 / マラリア / 自然免疫 / ワクチン / アジュバント / TLR9 / ヘモゾイン

Research Abstract

Although whole-parasite vaccine strategies for malaria infection have regained attention, their immunological mechanisms of action remain unclear. We find that immunization of mice with a crude blood stage extract of the malaria parasite Plasmodium falciparum elicits parasite antigen-specific immune responses via Toll-like receptor (TLR) 9 and that the malarial heme-detoxification byproduct, hemozoin (HZ), but not malarial DNA, produces a potent adjuvant effect. Malarial and synthetic (s)HZ bound TLR9 directly to induce conformational changes in the receptor. The adjuvant effect of sHZ depended on its method of synthesis and particle size. Although natural HZ acts as a TLR9 ligand, the adjuvant effects of synthetic HZ are independent of TLR9 or the NLRP3-inflammasome but are dependent on MyD88. The adjuvant function of sHZ was further validated in a canine antiallergen vaccine model. Thus, HZ can influence adaptive immune responses to malaria infection and may have therapeutic value in vaccine adjuvant development.

Research Products

• [Journal Article] Sechi AS. Biomedical polymers subvert dendritic cell function and adhesion through the activation of multiple Toll-like receptor signaling cascades (2010)
  • Author(s): Shokouhi B, Coban C, Hasirci V, Aydin E, Dhanasingh A, Shi N, Koyama S, Akira S, Zenke M
  • Journal Title: Biomaterials (in press)
• [Journal Article] TLR9 and Endogenous Adjuvants of the Whole Blood-stage Malaria Vaccine (2010)
  • Author(s): Coban C*, Horii T, Akira S, Ishii KJ
  • Journal Title: Review, Expert Reviews of Vaccines (in press)
• [Journal Article] The malarial metabolite hemozoin and its potential use as a vaccine adjuvant (2010)
  • Author(s): Cohan C*, Yagi M, Ohata K, Igari Y, Tsukui T, Horii T, Ishii KJ, Akira S
  • Journal Title: Review, Allergology International 59(2)(in press)
• [Journal Article] Plasmocytoid dendritic cells delineate immunogenicity of influenza vaccine subtypes (2010)
  • Author(s): Koyama S, Aoshi T, Tanimoto T, Kumagai Y, Kobiyama K, Tougan T, Sakurai K, Cohan C, Horii T, Akira S, Ishii KJ.
  • Journal Title: Science Translational Medicine Vol.2,Issue25
• [Journal Article] Immunogenicity of Whole Parasite Vaccines Against Plasmodium falciparum Involves Malarial Hemozoin and Host TLR9 (2010)
  • Author(s): Coban C, Igari Y, Yagi M, Reimer T, Koyama S, Aoshi T, Ohata K, Tsukui T, Takeshita F, Sakurai K, Ikegami T, Nakagawa A, Horii T, Nunez G, Ishii KJ, Akira S
  • Journal Title: Cell Host and Microbe 7(1) Pages: 50-61
• [Journal Article] Immunogenicity of whole-parasite vaccines against Plasmodium falciparum involves malarial hemozoin and host TLR9. (2010)
  • Author(s): Coban C, Igari Y, Yagi M, Reimer T, Koyama S, Aoshi T, Ohata K, Tsukui T, Takeshita F, Sakurai K, Ikegami T, Nakagawa A, Horii T, Nunez G, Ishii KJ, Akira S
  • Journal Title: Cell Host Microbe. 7 Pages: 50-61
  • Peer Reviewed
• [Journal Article] Immune interventions of human diseases through Toll-Like Receptors (2009)
  • Author(s): Coban C, Ishii KJ, Akira S
  • Journal Title: Review, Advances in Experimental Medicine and Biology 655 Pages: 63-80
• [Journal Article] Experimental Cerebral Malaria Progresses Independently of the Nlrp3 Inflammasome (2009)
  • Author(s): Reimer T, Shaw MH, Franchi L, Coban C Ishii KJ, Akira S, Horii T Rodriguez A, Nunez G
  • Journal Title: European Journal of Immunology 40(3) Pages: 764-9
• [Journal Article] Evidence for the Transmission of Plasmodium vivax in the Republic of the Congo, West Central Africa. (2009)
  • Author(s): Culleton R, Ndounga M, Zeyrek FY, Coban C, Casimiro PN. Takeo S, Tsuboi T. Yadava A, Carter R, Tanabe K.
  • Journal Title: Journal of Infectious Diseases 200(9) Pages: 1465-1469
  • NAID: 120006983581
• [Journal Article] Innate immune control of nucleic acid-based vaccine immunogenicity (2009)
  • Author(s): Koyama S, Coban C, Aoshi T, Horii T, Akira S, Ishii KJ
  • Journal Title: Review, Expert Review Vaccines 8(8) Pages: 1099-1107
• [Journal Article] Experimental cerebral malaria progresses independently of the Nlrp3 inflammasome. (2009)
  • Author(s): Reimer T, Shaw MH, Franchi L, Coban C, Ishii KJ, Akira S, Horii T, Rodriguez A, Nuiiez G.
  • Journal Title: Euro. J.Immunol. 40 Pages: 764-769
  • Peer Reviewed
• [Journal Article] Innate immune response to viral infection (2008)
  • Author(s): Koyama S. Ishii KJ, Coban C, Akira S
  • Journal Title: Review, Cytokine 43(3) Pages: 336-341
• [Journal Article] Host Innate Immune Receptors: Making Sense of Microbial Infections (2008)
  • Author(s): Ishii KJ Koyama S, Nakagawa A, Coban C, Akira S
  • Journal Title: Review, Cell Host and Microbe 3(6) Pages: 352-363
• [Journal Article] Molecular and cellular mechanisms of DNA vaccines. Review (2008)
  • Author(s): Coban C, Koyama S, Takeshita F, Akira S. Ishii KJ.
  • Journal Title: Human Vaccines 4(6) Pages: 453-456
• [Journal Article] Analysis of naturally acquired antibody responses to 19-kDa C-terminal region of the merozoite surface protein-1 of Plasmodium vivax from individuals in Sanliurfa, Turkey (2008)
  • Author(s): Yildiz Zeyrek F, Babaoglu A, Demirel S, Dirim Erdogan D, Ak M, Korkmaz M, Coban C.
  • Journal Title: American Journal of Tropical Medicine and Hygiene 78(5) Pages: 729-732
• [Journal Article] Tank-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines (2008)
  • Author(s): Ishii KJ, Kawagoe T, Koyama S, Matsui K, Kumar H, Kawai T, Uematsu S. Takeuchi O, Takeshita F, Coban C, Akira S
  • Journal Title: Nature 451(7179) Pages: 725-729
• [Journal Article] Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells (2008)
  • Author(s): Hisaeda H, Tetsutani K, Imai T, Moriya C, Tu L, Hamano S, Duan X, Chou B, Ishida H, Aramaki A, Shen J, Ishii KJ, Coban C, Akira S, Takeda K, Yasutomo K, Torii M, Himeno K
  • Journal Title: Journal of Immunology 180(4) Pages: 2496-2503
• [Journal Article] DNAワクチンのあらたな免疫学的作用機序 (2008)
  • Author(s): 青枝大貴、小山正平、チョバン・ジェヴァイア、石井健
  • Journal Title: 医学のあゆみ 227(5) Pages: 387-392
  • Peer Reviewed
• [Journal Article] ウイルスワクチン用のアジュバント (2008)
  • Author(s): 小山正平、ジェバイアチョバン、審良静男、堀井俊宏、石井健
  • Journal Title: VIRUS REPORT Vol.5No.1 Pages: 74-81
  • Peer Reviewed
• [Journal Article] Molecular and cellular mechanisms of DNA vaccines (2008)
  • Author(s): Coban C, Koyama S, Takeshita F, Akira S, Ishii KJ*.
  • Journal Title: Hum Vaccine 4(6) Pages: 453-6
  • Peer Reviewed
• [Journal Article] Host innate immune receptors and beyond : making sense of microbial infections (2008)
  • Author(s): Ishii KJ*, Koyama S, Nakagawa A, Coban C, Akira S.
  • Journal Title: Cell Host Microbe 3(6) Pages: 352-63
  • Peer Reviewed
• [Journal Article] Analysis of naturally acquired antibody responses to the 19-kd C-terminal region of merozoite surface proteinl of Plasmodium vivax from individuals in Sanliurfa, Turkey (2008)
  • Author(s): Zeyrek FY, Babaoglu A, Demirel S, Erdogan DD, AkM, Korkmaz M, Coban C.
  • Journal Title: Am J Trop Med Hyg 78(5) Pages: 729-32
  • Peer Reviewed
• [Presentation] Immunogenicity of whole parasite vaccine against Plasmodium falciparum involves malarial hemozoin and host TLR9 (2010)
  • Author(s): Coban C.
  • Organizer: 第3回原虫感染免疫研究会
  • Place of Presentation: 長崎大学・熱帯医学研究所
• [Presentation] Hemozoin, a malaria parasite nanocrystal: from malaria infection to vaccine adjuvant (2010)
  • Author(s): Coban C.
  • Organizer: Workshop on Current Trends in Molecular Nanobiosciences (Member of Organizing Committee)
  • Place of Presentation: Bilkent University, Ankara, TURKEY
• [Presentation] Innate immune system receptors and malaria (2010)
  • Author(s): Coban C.
  • Organizer: Winter School on Frontiers in Nanomedicine and Nanobiotechnology
  • Place of Presentation: Bilkent University, Ankara, TURKEY
• [Presentation] Immunogenicity of whole parasite vaccines against Plasmodium falciparum involves malarial hemozoin and host TLR9. (2009)
  • Author(s): Coban C, et al
  • Organizer: 日本免疫学会
  • Place of Presentation: 大阪
  • Year and Date: 2009-12-02
• [Presentation] Innate immune responses to malaria infection (2009)
  • Author(s): Coban C.
  • Organizer: 生化学若い研究者の会, 京都支部企画
  • Place of Presentation: 京大会館
  • Year and Date: 2009-11-28
• [Presentation] Host immune responses to malaria (2009)
  • Author(s): Coban C
  • Organizer: Bogazici University Department of Molecular Biology and Genetics
  • Place of Presentation: Istanbul, TURKEY
  • Year and Date: 2009-08-08
• [Presentation] TLR9 and the ASC-inflammasome differentially mediate the inflammatory and adjuvant effects of hemozoin, a heme-metabolite of the malaria parasite (2009)
  • Author(s): Coban C.
  • Organizer: 2009 JST-KICOS Cooperative Programme of IFReC and IVI: Regulation of Innate Immunity. International Vaccine Institute (IVI)
  • Place of Presentation: Seoul, KOREA
• [Presentation] Pathological roles of Toll-like receptor signaling on cerebral malaria (2006)
  • Author(s): Coban C, Ishii KJ, Uematsu S, Arisue N, Sato S, Yamamoto M, Kawai T, Takeuchi O, Hisaeda H, Horii T, Akira S
  • Organizer: BIOTEC
  • Year and Date: 2006-08-12
• [Presentation] Pathological roles of Toll-like receptor signaling on cerebral malaria (2006)
  • Author(s): Coban C, Ishii KJ, Uematsu S, Arisue N, Sato S, Yamamoto M, Kawai T, Takeuchi O, Hisaeda H, Horii T, Akira S
  • Organizer: AFRIMS
  • Place of Presentation: Bangkok, THAILAND
  • Year and Date: 2006-08-11
• [Presentation] Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin (2005)
  • Author(s): Coban C, Ishii KJ, Kawai T, Hemmi H, Sato S, Uematsu S, Yamamoto M, Takeuchi O, Itagaki S, Kumar N, Horii T, Akira S
  • Organizer: IMV 2nd International Conference on Immunopotentiators in Modern Vaccines
  • Place of Presentation: Malaga, SPAIN
  • Year and Date: 2005-05-12
• [Remarks]
  • URL: http://www.ifrec.osaka-u.ac.jo/jon/lahoratory/malariaimmunology/index.php
• [Remarks]
  • URL: http://www.ifrec.osaka-u.ac..jp/index.php
• [Patent(Industrial Property Rights)] A novel vaccine adjuvant. (2009)
  • Inventor(s): Ishii Ken, Akira Shizuo, Coban Cevayir, Tsukui Toshihiro
  • Industrial Property Rights Holder: 大阪大学、日本全薬工業
  • Filing Date: 2009-11-18
  • Overseas
• [Patent(Industrial Property Rights)] 新規アジュバント
  • Inventor(s): 審良静男、石井健、チョバンジェヴァイア、津久井利広
  • Industrial Property Rights Holder: 国立大学法人大阪大学、日本全薬工業
  • Industrial Property Number: 2007-285737