Background: Host immune responses at the site of Mycobacterium tuberculosis (Mtb) infection serve to contain the pathogen, but also mediate the pathogenesis of tuberculosis (TB) and onward transmission of infection. Based on the premise that active TB disease is predominantly a manifestation of immunopathology, we tested the hypothesis that immune responses at the site of host-pathogen interactions would reveal enrichment of immunopathologic responses in patients with active TB that were absent in individuals with equivalent immune memory for Mtb but without disease. Methods: In cohorts of patients with active TB and cured or latent infection, we undertook molecular profiling at the site of a tuberculin skin test to model in vivo host-pathogen interactions in Mtb infection. Genome-wide transcriptional differences were identified by differential gene expression analyses. Enrichment of immune cells and cytokine activity was derived using specific transcriptional modules. Findings were validated in independent cohorts of patients with active TB, as well as Mtb infected tissues. Results: Active TB in humans is associated with exaggerated IL-17A/F expression, accumulation of Th17 cells and IL-17A bioactivity, including increased neutrophil recruitment and matrix metalloproteinase-1 expression directly implicated in TB pathogenesis. These features discriminate recall responses in patients with active TB from those with cured or latent infection, and are also evident at the site of TB disease. Conclusions: Our data are consistent with a model in which elevated Th17 responses within tissues drive immunopathology and transmission in active TB, and support targeting of the IL-17A/F pathway in host-directed therapy for active TB.

中文翻译：

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夸大的体内IL-17反应可区分活动性结核病的召回反应

背景：结核分枝杆菌（Mtb）感染位点的宿主免疫反应不仅包含病原体，还介导了结核病（TB）的发病机理和感染的进一步传播。基于活动性结核病主要是免疫病理学的前提为前提，我们测试了以下假设：宿主免疫原-病原体相互作用部位的免疫应答将揭示活动性结核病患者的免疫病理学应答的丰富性，而这种免疫性结核病在具有相同免疫记忆的个体中不存在对于山结核病，但没有疾病。方法：在患有活动性结核病且已治愈或潜伏感染的患者队列中，我们在结核菌素皮肤试验部位进行了分子谱分析，以模拟Mtb感染的体内宿主-病原体相互作用。通过差异基因表达分析鉴定了全基因组的转录差异。使用特定的转录模块获得了免疫细胞的富集和细胞因子的活性。在患有活动性结核病以及Mtb感染组织的独立队列中验证了发现。结果：人类活动性结核病与夸大的IL-17A / F表达，Th17细胞蓄积和IL-17A生物活性有关，包括嗜中性粒细胞募集增加和基质金属蛋白酶-1表达直接与结核病发病有关。这些特征可将活动性结核病患者的召回反应与治愈或潜伏感染的患者区分开，并且在结核病发病部位也很明显。结论：