Immunogenicity of Whole-Parasite Vaccines against Plasmodium falciparum Involves Malarial Hemozoin and Host TLR9
Immunogenicity of Whole-Parasite Vaccines against Plasmodium falciparum Involves Malarial Hemozoin and Host TLR9
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DOI：
10.1016/j.chom.2009.12.003
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发表时间：
2010-01-21
影响因子：
30.3
通讯作者：
Akira, Shizuo
中科院分区：
文献类型：
--
作者：
Coban, Cevayir;Igari, Yoshikatsu;Akira, Shizuo
虽然疟疾感染的全寄生虫疫苗策略重新受到关注，但其免疫作用机制仍不清楚。我们发现，免疫小鼠的疟疾寄生虫恶性疟原虫elasticum寄生虫抗原特异性免疫反应的粗血液阶段提取物通过Toll样受体（TLR）9和疟疾血红素解毒副产物，疟原虫色素（HZ），但不是疟疾DNA，产生了有效的佐剂效应。疟疾和合成HZ直接结合TLR 9以诱导受体的构象变化。sHZ的佐剂效应与其合成方法和粒径大小有关。虽然天然HZ充当TLR 9配体，但合成HZ的佐剂作用不依赖于TLR 9或NLRP 3-炎性体，而是依赖于MyD 88。在犬抗变应原疫苗模型中进一步验证了sHZ的佐剂功能。因此，HZ可以影响对疟疾感染的适应性免疫应答，并且可能在疫苗佐剂开发中具有治疗价值。
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.