University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cell Host Microbe. 2013 Jan 16;13(1):42-53. doi: 10.1016/j.chom.2012.12.003. Epub 2013 Jan 3.
"Triple-defective" (3d) mice carrying a mutation in UNC93B1, a chaperone for the endosomal nucleic acid-sensing (NAS) Toll-like receptors TLR3, TLR7, and TLR9, are highly susceptible to Toxoplasma gondii infection. However, none of the single or even the triple NAS-TLR-deficient animals recapitulated the 3d susceptible phenotype to experimental toxoplasmosis. Investigating this further, we found that while parasite RNA and DNA activate innate immune responses via TLR7 and TLR9, TLR11 and TLR12 working as heterodimers are required for sensing and responding to Toxoplasma profilin. Consequently, the triple TLR7/TLR9/TLR11-deficient mice are highly susceptible to T. gondii infection, recapitulating the phenotype of 3d mice. Humans lack functional TLR11 and TLR12 genes. Consistently, human cells produce high levels of proinflammatory cytokines in response to parasite-derived RNA and DNA, but not to Toxoplasma profilin, supporting a more critical role for NAS-TLRs in human toxoplasmosis.
携带有 UNC93B1 基因突变的“三重缺陷”（3d）小鼠，UNC93B1 是内体核酸感应（NAS）Toll 样受体 TLR3、TLR7 和 TLR9 的伴侣蛋白，对刚地弓形虫感染高度易感。然而，即使是单一的或甚至是三重 NAS-TLR 缺陷的动物，也没有一种能够重现 3d 对实验性弓形体病的易感表型。进一步研究发现，虽然寄生虫 RNA 和 DNA 通过 TLR7 和 TLR9 激活先天免疫反应，但 TLR11 和 TLR12 作为异二聚体发挥作用，对于感应和响应刚地弓形虫原肌球蛋白是必需的。因此，三重 TLR7/TLR9/TLR11 缺陷小鼠对刚地弓形虫感染高度易感，重现了 3d 小鼠的表型。人类缺乏功能性 TLR11 和 TLR12 基因。一致地，人类细胞对寄生虫来源的 RNA 和 DNA 产生高水平的促炎细胞因子，但对刚地弓形虫原肌球蛋白没有反应，这支持 NAS-TLRs 在人类弓形体病中具有更关键的作用。
