Division of Infectious Disease and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
J Immunol. 2011 Aug 15;187(4):1903-11. doi: 10.4049/jimmunol.1003911. Epub 2011 Jul 13.
UNC93B1 associates with TLR3, 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 endosomal TLRs, are highly susceptible to infection with Trypanosoma cruzi. The enhanced parasitemia and mortality in 3d animals were associated with impaired proinflammatory response, including reduced levels of IL-12p40 and IFN-γ. Importantly, the phenotype of 3d mice was intermediary between MyD88(-/-) (highly susceptible) and TLR9(-/-) (moderately 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.
UNC93B1 与 TLR3、7 和 9 结合，介导它们从内质网向内体溶酶体的易位，从而允许微生物核酸的适当激活。我们发现，缺乏功能性 UNC93B1 以及功能性内体 TLR 的三重缺陷 3d 小鼠极易感染克氏锥虫。3d 动物中寄生虫血症和死亡率的增加与促炎反应受损有关，包括 IL-12p40 和 IFN-γ 水平降低。重要的是，3d 小鼠的表型介于 MyD88(-/-)（高度易感）和 TLR9(-/-)（中度易感）之间，表明宿主对 T. cruzi 的抗性涉及一种额外的 UN93B1 依赖性 TLR(s)。因此，我们的实验还表明，TLR7 是一种关键的先天免疫受体，参与寄生虫 RNA 的识别、树突状细胞中 IL-12p40 的诱导以及随后 T 淋巴细胞中 IFN-γ 的产生。此外，我们表明在 T. cruzi 感染后，三重 TLR3/7/9(-/-) 小鼠的表型与 3d 小鼠相似。这些数据表明，核酸感应 TLR 是宿主对 T. cruzi 初次感染的抗性的关键决定因素。
