The TLR2 is activated by sporozoites and suppresses intrahepatic rodent malaria parasite development.
The TLR2 is activated by sporozoites and suppresses intrahepatic rodent malaria parasite development.
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TLR2 被子孢子激活并抑制肝内啮齿动物疟疾寄生虫的发育
DOI：
10.1038/srep18239
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发表时间：
2015-12-15
影响因子：
4.6
通讯作者：
Xu W
中科院分区：
文献类型：
--
作者：
Zheng H;Tan Z;Zhou T;Zhu F;Ding Y;Liu T;Wu Y;Xu W
Toll样受体在启动针对入侵微生物的先天免疫反应中起着重要作用。尽管已有多个TLRs被报道参与了针对疟疾寄生虫血液期的先天免疫反应，但TLRs在红细胞前阶段的发育中的作用仍然很大程度上是未知的。在这里，我们发现子孢子及其裂解物能够显著激活TLR2，并以TLR2依赖的方式诱导巨噬细胞释放包括IL-6、单核细胞趋化蛋白-1和肿瘤坏死因子-α在内的促炎细胞因子。进一步的研究表明，TLR2同源二聚体或TLR2/1和TLR2/6异源二聚体均能识别子孢子及其裂解物，提示TLR2激动剂在子孢子中的复杂性。有趣的是，TLR2信号可以显著抑制约氏疟原虫红前红细胞阶段的发展，因为在TLR2和MyD88缺陷小鼠中，肝脏寄生虫载量和随后的寄生虫血症都显著增加。此外，在TLR2−/−小鼠中观察到的较高水平的寄生虫负荷被发现与肝脏中促炎症细胞因子的减少密切相关。因此，我们首次提供了子孢子可以激活TLR2信号，进而显著抑制肝内寄生虫的证据。这可能为我们设计预防性抗疟疾疗法提供新的线索。
TLRs (Toll-like receptors) play an important role in the initiation of innate immune responses against invading microorganisms. Although several TLRs have been reported to be involved in the innate immune response against the blood-stage of malaria parasites, the role of TLRs in the development of the pre-erythrocytic stage is still largely unknown. Here, we found that sporozoite and its lysate could significantly activate the TLR2 and induce macrophages to release proinflammatory cytokines, including IL-6, MCP-1 and TNF-α, in a TLR2-dependent manner. Further studies showed that sporozoite and its lysate could be recognized by either TLR2 homodimers or TLR2/1 and TLR2/6 heterodimers, implicating the complexity of TLR2 agonist in sporozoite. Interestingly, the TLR2 signaling can significantly suppress the development of the pre-erythrocytic stage ofPlasmodium yoelii, as both liver parasite load and subsequent parasitemia were significantly elevated in both TLR2- and MyD88-deficient mice. Additionally, the observed higher level of parasite burden in TLR2−/−mice was found to be closely associated with a reduction in proinflammatory cytokines in the liver. Therefore, we provide the first evidence that sporozoites can activate the TLR2 signaling, which in turn significantly inhibits the intrahepatic parasites. This may provide us with novel clues to design preventive anti-malaria therapies.