Mockenhaupt F P, Cramer J P, Hamann L, Stegemann M S, Eckert J, Oh Na-Ri, Otchwemah R N, Dietz E, Ehrhardt S, Schröder N W J, Bienzle U, Schumann R R
Institute of Tropical Medicine Berlin, Charité-Universitätsmedizin Berlin, Spandauer Damm 130, 14050 Berlin, Germany.
J Commun Dis. 2006 Mar;38(3):230-45.
Genetic host factors play a substantial role in susceptibility to and severity of malaria, which continues to cause at least one million deaths per year. Recently, members of the toll-like receptor (TLR) family have been shown to be involved in recognition of the etiologic organism Plasmodium falciparum: The glycosylphosphatidylinisitol anchor induces signaling in host cells via TLR-2 and -4, while hemozoin-induced immune activation involves TLR-9. Binding of microbial ligands to the respective TLRs triggers the release of pro-inflammatory cytokines via the TLR/IL-1 receptor (TIR) domain and may contribute to the host response, including pro-inflammatory cytokine induction and malarial fever. In a case-control study among 870 Ghanaian children, we examined the influence of TLR-2, -4, and -9 polymorphisms in susceptibility to severe malaria. TLR-2 variants common in Caucasians and Asians were completely absent. However, we found a new, rare mutation (Leu658Pro), which impairs signaling via TLR-2. We failed to detect any polymorphisms within the TLR-9/interleukin-1 receptor domain. Two frequent TLR-9 promoter polymorphisms did not show a clear association with malaria severity. In contrast, the TLR-4-Asp299Gly variant occurred at a high rate of 17.6% in healthy controls, and was even more frequent in severe malaria patients (24.1%, p<0.05). Likewise, TLR-4-Thr399Ile was seen in 2.4% of healthy children and in 6.2% of patients (p=0.02). TLR-4-Asp299Gly and TLR-4-Thr399Ile conferred an 1.5- and 2.6-fold increased risk of severe malaria, respectively. These findings suggest TLR4-mediated responses to malaria in vivo and TLR-4 polymorphisms to be associated with disease manifestation. However some gray areas also suggest the scope for further improvements.
遗传宿主因素在疟疾易感性和严重程度方面起着重要作用，疟疾每年仍导致至少100万人死亡。最近，Toll样受体（TLR）家族成员已被证明参与对致病生物体恶性疟原虫的识别：糖基磷脂酰肌醇锚定物通过TLR-2和-4在宿主细胞中诱导信号传导，而疟原虫血红素诱导的免疫激活涉及TLR-9。微生物配体与各自的TLR结合通过TLR/白细胞介素-1受体（TIR）结构域触发促炎细胞因子的释放，并可能有助于宿主反应，包括促炎细胞因子的诱导和疟疾发热。在一项针对870名加纳儿童的病例对照研究中，我们研究了TLR-2、-4和-9多态性对严重疟疾易感性的影响。在白种人和亚洲人中常见的TLR-2变体完全不存在。然而，我们发现了一种新的罕见突变（Leu658Pro），它损害了通过TLR-2的信号传导。我们未能在TLR-9/白细胞介素-1受体结构域内检测到任何多态性。两种常见的TLR-9启动子多态性与疟疾严重程度没有明显关联。相比之下，TLR-4-Asp299Gly变体在健康对照中的发生率高达17.6%，在严重疟疾患者中更为常见（24.1%，p<0.05）。同样，TLR-4-Thr399Ile在2.4%的健康儿童和6.2%的患者中出现（p=0.02）。TLR-4-Asp299Gly和TLR-4-Thr399Ile分别使严重疟疾的风险增加了1.5倍和2.6倍。这些发现表明TLR4介导的体内对疟疾的反应以及TLR-4多态性与疾病表现相关。然而，一些灰色地带也表明还有进一步改进的空间。
