Tsenova L, Bergtold A, Freedman V H, Young R A, Kaplan G
Laboratory of Cellular Physiology and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Proc Natl Acad Sci U S A. 1999 May 11;96(10):5657-62. doi: 10.1073/pnas.96.10.5657.
The pathogenesis of tuberculous meningitis, a devastating complication of tuberculosis in man, is poorly understood. We previously reported that rabbits with experimental tuberculous meningitis were protected from death by a combination of antibiotics and thalidomide therapy. Survival was associated with inhibition of tumor necrosis factor alpha (TNF-alpha) production by thalidomide. To test whether cerebrospinal fluid (CSF) levels of TNF-alpha correlated with pathogenesis, the response of rabbits infected in the central nervous system (CNS) with various mycobacterial strains was studied. CNS infection with Mycobacterium bovis Ravenel, M. bovis bacillus Calmette-Guérin (BCG) Pasteur, and M. bovis BCG Montreal were compared. M. bovis Ravenel induced the highest levels of TNF-alpha in the CSF in association with high leukocytosis, protein accumulation, and severe meningeal inflammation. BCG Pasteur had intermediate effects, and BCG Montreal was the least virulent. In addition, M. bovis Ravenel numbers were highest in the brain and CSF and the bacilli also disseminated more efficiently to distant organs, compared with BCG Pasteur and BCG Montreal. In subsequent experiments, rabbits were infected with either recombinant M. bovis BCG Montreal (vector), or BCG Montreal expressing the murine gene for TNF-alpha (BCG mTNF-alpha). BCG Montreal was rendered virulent by the expression of murine TNF-alpha, as demonstrated by high CSF leukocytosis, high protein accumulation, severe meningeal inflammation, persistent bacillary load, and progressive clinical deterioration. Taken together, these results demonstrate that the level of TNF-alpha produced during mycobacterial CNS infection determines, at least in part, the extent of pathogenesis.
结核性脑膜炎是人类结核病的一种毁灭性并发症，其发病机制尚不清楚。我们之前报道，联合使用抗生素和沙利度胺治疗可保护患有实验性结核性脑膜炎的兔子免于死亡。存活与沙利度胺抑制肿瘤坏死因子α（TNF-α）的产生有关。为了测试脑脊液（CSF）中TNF-α水平是否与发病机制相关，我们研究了用各种分枝杆菌菌株感染中枢神经系统（CNS）的兔子的反应。比较了用牛分枝杆菌拉韦内尔株、卡介苗巴斯德株和卡介苗蒙特利尔株感染中枢神经系统的情况。牛分枝杆菌拉韦内尔株在脑脊液中诱导出最高水平的TNF-α，同时伴有白细胞增多、蛋白质积聚和严重的脑膜炎症。卡介苗巴斯德株的作用居中，而卡介苗蒙特利尔株的毒性最小。此外，与卡介苗巴斯德株和卡介苗蒙特利尔株相比，牛分枝杆菌拉韦内尔株在脑和脑脊液中的数量最高，并且杆菌也更有效地扩散到远处器官。在随后的实验中，兔子分别感染了重组卡介苗蒙特利尔株（载体）或表达小鼠TNF-α基因的卡介苗蒙特利尔株（卡介苗mTNF-α）。表达小鼠TNF-α使卡介苗蒙特利尔株具有毒性，表现为脑脊液白细胞增多、蛋白质积聚高、脑膜炎症严重、细菌载量持续存在以及临床病情逐渐恶化。综上所述，这些结果表明，分枝杆菌中枢神经系统感染期间产生的TNF-α水平至少部分决定了发病机制的程度。
