title: Immunogenicity of whole-parasite vaccines against Plasmodium falciparum involves malarial hemozoin and host TLR9.
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.
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors.forename: Cevayir
authors.initials: C
authors.lastname: Coban
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Igari
authors.forename: Masanori
authors.initials: M
authors.lastname: Yagi
authors.forename: Thornik
authors.initials: T
authors.lastname: Reimer
authors.forename: Shohei
authors.initials: S
authors.lastname: Koyama
authors.forename: Taiki
authors.initials: T
authors.lastname: Aoshi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ohata
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tsukui
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Takeshita
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sakurai
authors.forename: Takahisa
authors.initials: T
authors.lastname: Ikegami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakagawa
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Horii
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nuñez
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D006420:Hemeproteins / Q000494:pharmacology*; D006967:Hypersensitivity / Q000517:prevention & control; D017780:Malaria Vaccines / Q000276:immunology*; D016778:Malaria, Falciparum / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010047:Ovalbumin / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology*; D011485:Protein Binding; D011487:Protein Conformation; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000172:deficiency
chemical_list: D000276:Adjuvants, Immunologic; D000913:Antibodies, Protozoan; D002352:Carrier Proteins; D006420:Hemeproteins; D017780:Malaria Vaccines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C020753:hemozoin; D010047:Ovalbumin