Mycobacterium tuberculosis (Mtb) is the causative agent of the infectious disease tuberculosis (TB), which is a leading cause of death worldwide. Approximately one fourth of the world's population is infected with Mtb. A major unresolved question is delineating the inducers of protective long-lasting immune response without inducing overt, lung inflammation. Previous studies have shown that the presence of inducible Bronchus-Associated Lymphoid Tissue (iBALT) correlate with protection from Mtb infection. In this study, we hypothesized that specific Mtb factors could influence the formation of iBALT, thus skewing the outcome of TB disease. We infected non-human primates (NHPs) with a transposon mutant library of Mtb, and identified specific Mtb mutants that were over-represented within iBALT-containing granulomas. A major pathway reflected in these mutants was Mtb cell wall lipid transport and metabolism. We mechanistically addressed the function of one such Mtb mutant lacking mycobacteria membrane protein large 7 (MmpL7), which transports phthiocerol dimycocerosate (PDIM) to the mycobacterial outer membrane (MOM). Accordingly, murine aerosol infection with the Mtb mutant Δmmpl7 correlated with increased iBALT-containing granulomas. Our studies showed that the Δmmpl7 mutant lacking PDIMs on the surface overexpressed diacyl trehaloses (DATs) in the cell wall, which altered the cytokine/chemokine production of epithelial and myeloid cells, thus leading to a dampened inflammatory response. Thus, this study describes an Mtb specific factor that participates in the induction of iBALT formation during TB by directly modulating cytokine and chemokine production in host cells.

结核分枝杆菌(甲基叔丁基醚) 是传染性疾病结核病 (TB) 的病原体，该病是全球主要的死亡原因。世界上大约四分之一的人口感染了甲基叔丁基醚. 一个尚未解决的主要问题是在不引起明显肺部炎症的情况下描述保护性持久免疫反应的诱导剂。先前的研究表明，诱导型支气管相关淋巴组织 (iBALT) 的存在与保护甲基叔丁基醚感染。在本研究中，我们假设特定甲基叔丁基醚因素可能会影响 iBALT 的形成，从而扭曲结核病的结果。我们用转座子突变文库感染了非人类灵长类动物 (NHP)甲基叔丁基醚，并确定了具体的甲基叔丁基醚在含有 iBALT 的肉芽肿中过度表达的突变体。这些突变体中反映的主要途径是甲基叔丁基醚细胞壁脂质转运和代谢。我们机械地解决了一个这样的功能甲基叔丁基醚缺乏分枝杆菌膜蛋白大7的突变体（MmpL7)，它将苯硫酚二霉菌酸 (PDIM) 转运到分枝杆菌外膜 (MOM)。因此，鼠气溶胶感染与甲基叔丁基醚突变体Δmmpl7与增加的含有 iBALT 的肉芽肿相关。我们的研究表明，Δmmpl7表面缺乏 PDIM 的突变体在细胞壁中过表达二酰基海藻糖 (DAT)，这改变了上皮细胞和骨髓细胞的细胞因子/趋化因子的产生，从而导致炎症反应减弱。因此，本研究描述了一个甲基叔丁基醚通过直接调节宿主细胞中细胞因子和趋化因子的产生，参与诱导 TB 期间 iBALT 形成的特定因子。