Requirement of UNC93B1 reveals a critical role for TLR7 in host resistance to primary infection with Trypanosoma cruzi.
Requirement of UNC93B1 reveals a critical role for TLR7 in host resistance to primary infection with Trypanosoma cruzi.
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DOI：
10.4049/jimmunol.1003911
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发表时间：
2011-08-15
期刊：
影响因子：
--
通讯作者：
Gazzinelli RT
中科院分区：
文献类型：
--
作者：
Caetano BC;Carmo BB;Melo MB;Cerny A;dos Santos SL;Bartholomeu DC;Golenbock DT;Gazzinelli RT
UNC 93 B1与Toll样受体（TLR）3、7和9相关，介导其从内质网易位至内溶酶体，从而允许微生物核酸的适当激活。我们发现，缺乏功能性UNC 93 B1以及功能性内体TLR的三重缺陷“3d”小鼠对克氏锥虫感染高度敏感。在3d动物中增加的寄生虫血症和死亡率与受损的促炎反应相关，包括降低的IL-12 p40和IFN-γ水平。重要的是，3d小鼠的表型介于MyD 88 −/−（高度敏感）和TLR 9 −/−（较不敏感）之间，表明额外的UN 93 B1依赖性TLR参与宿主对T的抗性。克鲁兹因此，我们的实验还揭示了TLR 7是一种关键的先天性免疫受体，参与识别寄生虫RNA，通过树突状细胞诱导IL-12 p40，以及随后通过T淋巴细胞诱导IFN-γ。此外，我们还证明了在T. cruzi感染三重TLR 3/7/9−/−小鼠具有与3d小鼠相似的表型。这些数据表明，核酸敏感TLR是宿主对T.克鲁兹
UNC93B1 associates with Toll-Like Receptor (TLR) 3, 7 and 9, mediating their translocation from the endoplasmic reticulum to the endolysosome, thus allowing proper activation by microbial nucleic acids. We found that the triple deficient ‘3d’ mice, which lack functional UNC93B1 as well as functional endossomal TLRs, are highly susceptible to infection with Trypanosoma cruzi. The enhanced parasitemia and mortality in 3d animals were associated with impaired pro-inflammatory response, including reduced levels of IL-12p40 and IFN-γ. Importantly, the phenotype of 3d mice was intermediary between MyD88−/− (highly susceptible) and TLR9−/− (less susceptible), indicating the involvement of an additional UN93B1-dependent-TLR(s) on host resistance to T. cruzi. Hence, our experiments also revealed that TLR7 is a critical innate immune receptor involved in recognition of parasite RNA, induction of IL-12p40 by dendritic cells, and consequent IFN-γ by T lymphocytes. Furthermore, we show that upon T. cruzi infection triple TLR3/7/9−/− mice had similar phenotype than 3d mice. These data imply that the nucleic acid-sensing TLRs are critical determinants of host resistance to primary infection with T. cruzi.
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影响因子：
3.1
作者：
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通讯作者：
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影响因子：
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通讯作者：
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