Immunogenicity of whole-parasite vaccines against Plasmodium falciparum involves malarial hemozoin and host TLR9.
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.
Coban
Cevayir
C
Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Igari
Yoshikatsu
Y
Yagi
Masanori
M
Reimer
Thornik
T
Koyama
Shohei
S
Aoshi
Taiki
T
Ohata
Keiichi
K
Tsukui
Toshihiro
T
Takeshita
Fumihiko
F
Sakurai
Kazuo
K
Ikegami
Takahisa
T
Nakagawa
Atsushi
A
Horii
Toshihiro
T
Nuñez
Gabriel
G
Ishii
Ken J
KJ
Akira
Shizuo
S
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
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