Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX, USA.
University of New England, College of Dental Medicine, Portland, ME, USA.
Tuberculosis (Edinb). 2019 May;116S:S131-S137. doi: 10.1016/j.tube.2019.04.021. Epub 2019 May 3.
Mycobacterium tuberculosis (Mtb) is a facultative intracellular pathogen that infects macrophages where it avoids elimination by interfering with host defense mechanisms, including phago-lysosome fusion. Endosomal Toll-like receptors (TLRs) generate Type I Interferons (IFNs), which are associated with active tuberculosis (TB). We aimed to explore if DNA from different Mtb lineages lead to differences in the inflammatory response of human monocytic/macrophage cells. THP-1 cells which express two inducible reporter constructs for interferons (IFNs) as well as for NF-κB, were stimulated via endosomal delivery of Mtb DNA as a nanocomplex with PEI. DNA from different Mtb phylogenetic lineages elicited differential inflammatory responses in human macrophages. An initial relatively weak IRF-mediated response to DNA from HN878 and H37Rv increased if the cells were pre-treated with Vitamin D (Vit D) for 72 h. RNAseq of THP-1 under different transformation conditions showed that pre-treatment with Vit D upregulated several TLR9 variants, as well as genes involved in inflammatory immune response to infection, immune cell activation, Type I IFN regulation, and regulation of inflammation. Vit D appears to be important in increasing low IRF responses to DNA from certain lineages of Mtb. Variations in the IRF-mediated response to DNA derived from different Mtb genotypes are potentially important in the pathogenesis of tuberculosis since Type I IFN responses are associated with active disease. The role of Vit D in these responses could also translate into future therapeutic approaches.
结核分枝杆菌（Mtb）是一种兼性细胞内病原体，它感染巨噬细胞，通过干扰宿主防御机制，包括吞噬体-溶酶体融合，从而避免被清除。内体 Toll 样受体（TLRs）产生 I 型干扰素（IFNs），与活动性结核病（TB）有关。我们旨在探索不同结核分枝杆菌谱系的 DNA 是否会导致人单核/巨噬细胞炎症反应的差异。THP-1 细胞表达两种可诱导的干扰素（IFNs）和 NF-κB 的报告基因构建体，通过与 PEI 形成纳米复合物的方式，通过内体递送来刺激 Mtb DNA。来自不同结核分枝杆菌进化枝的 DNA 在人类巨噬细胞中引发了不同的炎症反应。最初对来自 HN878 和 H37Rv 的 DNA 的相对较弱的 IRF 介导的反应，如果细胞用维生素 D（Vit D）预处理 72 小时，则会增加。在不同转化条件下的 THP-1 的 RNAseq 显示，Vit D 预处理上调了几种 TLR9 变体，以及参与感染、免疫细胞激活、I 型 IFN 调节和炎症调节的炎症免疫反应的基因。Vit D 似乎在增加对某些结核分枝杆菌谱系 DNA 的低 IRF 反应方面很重要。对来自不同结核分枝杆菌基因型的 DNA 的 IRF 介导反应的差异可能在结核病发病机制中很重要，因为 I 型 IFN 反应与活动性疾病有关。Vit D 在这些反应中的作用也可能转化为未来的治疗方法。
