Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
Cell Host Microbe. 2010 Jan 21;7(1):50-61. doi: 10.1016/j.chom.2009.12.003.
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.
虽然针对疟疾感染的全寄生虫疫苗策略重新引起了关注，但它们的免疫作用机制仍不清楚。我们发现，用疟原虫恶性疟原虫的粗血阶段提取物免疫小鼠可通过 Toll 样受体（TLR）9 引发寄生虫抗原特异性免疫反应，并且疟原虫血红素解毒副产物血影蛋白（HZ）而不是疟原虫 DNA 产生强大的佐剂效应。疟原虫和合成（s）HZ 直接与 TLR9 结合，诱导受体构象发生变化。sHZ 的佐剂效应取决于其合成方法和粒径。尽管天然 HZ 作为 TLR9 配体起作用，但合成 HZ 的佐剂作用与 TLR9 或 NLRP3 炎性小体无关，而是依赖于 MyD88。sHZ 的佐剂功能在犬过敏原疫苗模型中得到了进一步验证。因此，HZ 可以影响对疟疾感染的适应性免疫反应，并且在疫苗佐剂开发中可能具有治疗价值。
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