MyD88/IL-18-dependent pathways rather than TLRs control early parasitaemia in non-lethal Plasmodium yoelii infection
MyD88/IL-18-dependent pathways rather than TLRs control early parasitaemia in non-lethal Plasmodium yoelii infection
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DOI：
10.1016/j.micinf.2008.07.024
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发表时间：
2008-10-01
影响因子：
5.8
通讯作者：
Jacobs, Thomas
中科院分区：
文献类型：
--
作者：
Cramer, Jakob P.;Lepenies, Bernd;Jacobs, Thomas
恶性疟原虫GPI通过诱导细胞因子释放参与疟疾病理。它已被证明通过TLR2和TLR4在体外被识别。然而，先前关于tlr在寄生虫清除或体内病理中的作用的研究结果是相互矛盾的。因此，我们利用约氏p.o elii感染模型分析了tlr信号传导对保护的影响。单TLRs缺乏和三tlr2 /4/9缺乏对寄生虫病无影响。相比之下，缺乏连接蛋白MyD88的小鼠更容易受到约氏疟原虫感染，因为它们在感染的早期阶段表现出更高的寄生虫血症和更高的致死率。这种表型主要是由IL-18信号传导受损引起的，因为与野生型对照小鼠相比，IL-18缺陷小鼠的寄生血症在P. yoelii感染的早期时间点也有所增加。然而，il -18缺失小鼠未见致死性。由于在P. yoeli感染期间，IL-1R缺陷小鼠的寄生虫血症也略有增加，因此IL-1R信号受损在较小程度上导致myd88缺陷小鼠的易感性增加。这些发现与MyD88-和il -18缺陷小鼠的ifn - γ产生减少相关，但与tlr2 /4/9缺陷小鼠无关。我们得出结论，在我们的模型中，主要依赖IL-18/ myd88的信号通路对寄生虫的早期控制很重要，而不是tlr2 /4/9信号通路。(C) 2008 Elsevier Masson SAS。版权所有。
Plasmodium falciparum GPI contributes to malaria pathology by inducing cytokine release. It has been shown to be recognized through TLR2 and to a lesser extent TLR4 in vitro. However, previous findings on the role of TLRs in parasite clearance or pathology in vivo are conflicting. Thus, we analyzed the impact of TLR-signalling on protection using the P. yoelii infection model. Deficiency of single TLRs as well as triple TLR2/4/9-deficiency had no impact on parasitaemia. In contrast, mice deficient for the adaptor protein MyD88 were more susceptible to P. yoelii infection in that they exhibited an increased parasitaemia in the early phase of the infection and a higher lethality. This phenotype was caused mainly by impaired IL-18 signalling since parasitaemia in IL-18-deficient mice was also increased at early time points during P. yoelii infection compared to wild-type control mice. However, no lethality was observed in IL-18-deficient mice. Since parasitaemia in IL-1R-deficient mice was also slightly increased during P. yoelii infection, impaired IL-1R signalling contributed to the increased susceptibility of MyD88-deficient mice to a lesser extent. These findings correlated with a reduced IFN-gamma production in MyD88- and IL-18-deficient mice, but not in TLR2/4/9-deficient mice. We conclude that mainly IL-18/MyD88-dependent signalling but not TLR2/4/9-signal ling is important for early parasite control in our model. (C) 2008 Elsevier Masson SAS. All rights reserved.