Be Nicholas A, Lamichhane Gyanu, Grosset Jacques, Tyagi Sandeep, Cheng Qi-Jian, Kim Kwang Sik, Bishai William R, Jain Sanjay K
Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
J Infect Dis. 2008 Nov 15;198(10):1520-8. doi: 10.1086/592447.
Tuberculosis of the central nervous system (CNS) is a serious, often fatal disease primarily affecting young children. It develops after hematogenous dissemination and subsequent invasion of the CNS by Mycobacterium tuberculosis. The microbial determinants involved in CNS disease are poorly characterized.
Hematogenously disseminated M. tuberculosis infection was simulated in BALB/c mice by intravenous challenge. Bacteria were recovered using standard culture techniques. Host immune response to M. tuberculosis infection was assessed by histopathological and cytokine profile analysis. By means of a pooled infection with genotypically defined M. tuberculosis mutants, bacterial genes required for invasion or survival were determined in the CNS and lung tissue.
M. tuberculosis were detected in whole mouse brains as early as 1 day after intravenous infection and at all time points assessed thereafter. No significant immune response was elicited in the infected brain tissue, compared with extensive inflammation in the infected lung tissue at the same time point. We identified mutants for 5 M. tuberculosis genes (Rv0311, Rv0805, Rv0931c, Rv0986, and MT3280) with CNS-specific phenotypes, absent in lung tissue.
We have identified CNS-specific M. tuberculosis genes involved in the pathogenesis of tuberculosis. Further characterization of these genes will help in understanding the microbial pathogenesis of CNS tuberculosis.
中枢神经系统（CNS）结核是一种严重的、通常致命的疾病，主要影响幼儿。它在结核分枝杆菌经血行播散并随后侵入中枢神经系统后发生。参与中枢神经系统疾病的微生物决定因素目前尚不清楚。
通过静脉注射在BALB/c小鼠中模拟经血行播散的结核分枝杆菌感染。使用标准培养技术回收细菌。通过组织病理学和细胞因子谱分析评估宿主对结核分枝杆菌感染的免疫反应。通过与基因定义的结核分枝杆菌突变体进行混合感染，确定中枢神经系统和肺组织中侵袭或存活所需的细菌基因。
静脉感染后1天，在整个小鼠脑中即可检测到结核分枝杆菌，且在随后评估的所有时间点均能检测到。与同一时间点感染的肺组织中的广泛炎症相比，感染的脑组织中未引发明显的免疫反应。我们鉴定出5个结核分枝杆菌基因（Rv0311、Rv0805、Rv0931c、Rv0986和MT3280）的突变体，这些突变体在肺组织中不存在，但具有中枢神经系统特异性表型。
我们已经鉴定出参与结核病发病机制的中枢神经系统特异性结核分枝杆菌基因。对这些基因的进一步表征将有助于理解中枢神经系统结核的微生物发病机制。
