Malaria primes the innate immune response due to interferon-γ induced enhancement of toll-like receptor expression and function
Malaria primes the innate immune response due to interferon-γ induced enhancement of toll-like receptor expression and function
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DOI：
10.1073/pnas.0809742106
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发表时间：
2009-04-07
影响因子：
11.1
通讯作者：
Gazzinelli, Ricardo T.
中科院分区：
文献类型：
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作者：
Franklin, Bernardo S.;Parroche, Peggy;Gazzinelli, Ricardo T.
疟疾引起的败血症与强烈的促炎性细胞分裂素血症有关，其潜在机制尚不清楚。已有研究表明，人感染恶性疟原虫原虫后，Toll样受体(TLR)介导的促炎反应。然而，这种现象在自然感染期间的相关性，以及更重要的是，疟疾介导TLR高反应性的机制尚不清楚。在这里，我们显示了在自然感染恶性疟原虫期间发热患者的TLR反应增强。微阵列分析表明，在上调的基因中，有非常高比例的基因，包括涉及TLR信号的基因，具有干扰素诱导转录因子的位点。为了进一步确定疟疾介导的“启动”机制，我们用查鲍迪疟原虫感染了小鼠。人类数据很好地预测了我们在啮齿动物疟疾模型中观察到的情况。疟疾诱导的TLR反应的启动与TLR9、MyD88和干扰素伽马依赖的TLR mRNA表达增加相关。急性感染的WT小鼠对脂多糖诱导的致死性高度敏感，而TLR9(-/-)、IL12(-/-)和更大程度上，干扰素-γ(-/-)小鼠受到保护。我们的数据提供了前所未有的证据表明，TLR9和MyD88对于启动IL12和干扰素伽马反应是必不可少的，并有利于宿主对TLR激动剂的高反应性，从而导致促炎细胞因子的过度产生和急性疟疾的败血症样症状。
Malaria-induced sepsis is associated with an intense proinflammatory cytokinemia for which the underlying mechanisms are poorly understood. It has been demonstrated that experimental infection of humans with Plasmodium falciparum primes Toll-like receptor (TLR)-mediated proinflammatory responses. Nevertheless, the relevance of this phenomenon during natural infection and, more importantly, the mechanisms by which malaria mediates TLR hyperresponsiveness are unclear. Here we show that TLR responses are boosted in febrile patients during natural infection with P. falciparum. Microarray analyses demonstrated that an extraordinary percentage of the up-regulated genes, including genes involving TLR signaling, had sites for IFN-inducible transcription factors. To further define the mechanism involved in malaria-mediated "priming,'' we infected mice with Plasmodium chabaudi. The human data were remarkably predictive of what we observed in the rodent malaria model. Malaria-induced priming of TLR responses correlated with increased expression of TLR mRNA in a TLR9-, MyD88-, and IFN gamma-dependent manner. Acutely infected WT mice were highly susceptible to LPS-induced lethality while TLR9(-/-), IL12(-/-) and to a greater extent, IFN gamma(-/-) mice were protected. Our data provide unprecedented evidence that TLR9 and MyD88 are essential to initiate IL12 and IFN gamma responses and favor host hyperresponsiveness to TLR agonists resulting in overproduction of proinflammatory cytokines and the sepsis-like symptoms of acute malaria.