Okamoto Yuko, Fujita Yukiko, Naka Takashi, Hirai Manabu, Tomiyasu Ikuko, Yano Ikuya
Japan BCG Central Laboratory, 3-1-5 Matsuyama, Kiyose-shi, Tokyo 204-0022, Japan.
Microb Pathog. 2006 Jun;40(6):245-53. doi: 10.1016/j.micpath.2006.02.002. Epub 2006 Apr 19.
Virulence mechanism of infection with Mycobacterium tuberculosis is currently focused to be clarified in the context of cell surface lipid molecule. Comparing two mycobacterial glycolipids, we observed toxicity and prominent granulomatogenic activity of trehalose 6,6'-dimycolate (TDM) injection in mice, evident by delayed body weight gain and histological observations, whereas 2,3,6,6'-tetraacyl trehalose 2'-sulfate (SL) was non-toxic and non-granulomatogenic. Likewise, TDM but not SL caused temporarily, but marked increase of lung indices, indicative of massive granuloma formation. Interestingly, co-administration of TDM and SL prevented these symptoms distinctively and SL inhibited TDM-induced release of tumor necrosis factor alpha (TNF-alpha) in a dose-dependent manner. Histological findings and organ index changes also showed marked inhibition of TDM induced granuloma formation by co-administration of SL. Simultaneous injection of SL together with TDM was highly effective for this protection, as neither injection 1h before nor after TDM injection showed highly inhibitory. In parallel studies on a cellular level, TDM elicited strong TNF-alpha release from alveolar but not from peritoneal macrophages in vitro. This effect was blocked when alveolar macrophages were incubated in wells simultaneously coated with TDM and SL, indicating that SL suppresses TDM-induced TNF-alpha release from macrophages. Our results suggest a novel mechanism by which SL could contribute to virulence at early stage of mycobacterial infection or stimulation with the glycolipids by counteracting the immunopotentiating effect of TDM.
目前，结核分枝杆菌感染的毒力机制主要聚焦于细胞表面脂质分子的背景下进行阐明。比较两种分枝杆菌糖脂，我们观察到在小鼠中注射海藻糖6,6'-二霉菌酸酯（TDM）具有毒性和显著的肉芽肿形成活性，这通过体重增加延迟和组织学观察得以证实，而2,3,6,6'-四酰基海藻糖2'-硫酸盐（SL）则无毒且不具有肉芽肿形成活性。同样，TDM而非SL会暂时导致肺指数显著增加，这表明有大量肉芽肿形成。有趣的是，TDM和SL共同给药能显著预防这些症状，并且SL以剂量依赖的方式抑制TDM诱导的肿瘤坏死因子α（TNF-α）释放。组织学发现和器官指数变化也表明，SL共同给药可显著抑制TDM诱导的肉芽肿形成。TDM与SL同时注射对这种保护作用非常有效，因为在TDM注射前1小时或后注射均未显示出高度抑制作用。在细胞水平的平行研究中，TDM在体外能诱导肺泡巨噬细胞而非腹膜巨噬细胞强烈释放TNF-α。当肺泡巨噬细胞在同时包被有TDM和SL的孔中孵育时，这种效应被阻断，这表明SL抑制了TDM诱导的巨噬细胞TNF-α释放。我们的结果提示了一种新机制，即SL可能通过抵消TDM的免疫增强作用，在分枝杆菌感染早期或用糖脂刺激时对毒力产生影响。
