Lenaerts Anne J, Hoff Donald, Aly Sahar, Ehlers Stefan, Andries Koen, Cantarero Luis, Orme Ian M, Basaraba Randall J
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
Antimicrob Agents Chemother. 2007 Sep;51(9):3338-45. doi: 10.1128/AAC.00276-07. Epub 2007 May 21.
The lengthy chemotherapy of tuberculosis reflects the ability of a small subpopulation of Mycobacterium tuberculosis bacteria to persist in infected individuals. To date, the exact location of these persisting bacteria is not known. Lung lesions in guinea pigs infected with M. tuberculosis have striking similarities, such as necrosis, mineralization, and hypoxia, to natural infections in humans. Guinea pigs develop necrotic primary lesions after aerosol infection that differ in their morphology compared to secondary lesions resulting from hematogenous dissemination. In infected guinea pigs conventional therapy for tuberculosis during 6 weeks reduced the bacterial load by 1.7 logs in the lungs and, although this completely reversed lung inflammation associated with secondary lesions, the primary granulomas remained largely unaffected. Treatment of animals with the experimental drug R207910 (TMC207) for 6 weeks was highly effective with almost complete eradication of the bacteria throughout both the primary and the secondary lesions. Most importantly, the few remnants of acid-fast bacilli remaining after R207910 treatment were to be found extracellular, in a microenvironment of residual primary lesion necrosis with incomplete dystrophic calcification. This zone of the primary granuloma is hypoxic and is morphologically similar to what has been described for human lung lesions. These results show that this acellular rim may, therefore, be a primary location of persisting bacilli withstanding drug treatment.
结核病的长期化疗反映了一小部分结核分枝杆菌在受感染个体中持续存在的能力。迄今为止，这些持续存在的细菌的确切位置尚不清楚。感染结核分枝杆菌的豚鼠肺部病变与人类自然感染有显著相似之处，如坏死、矿化和缺氧。豚鼠经气溶胶感染后会形成坏死性原发性病变，其形态与血行播散导致的继发性病变不同。在感染的豚鼠中，为期6周的常规结核病治疗使肺部细菌载量降低了1.7个对数，尽管这完全逆转了与继发性病变相关的肺部炎症，但原发性肉芽肿基本未受影响。用实验药物R207910（TMC207）对动物进行6周治疗非常有效，几乎完全根除了原发性和继发性病变中的细菌。最重要的是，在R207910治疗后残留的少数抗酸杆菌残留在细胞外，处于原发性病变坏死残留且营养不良性钙化不完全的微环境中。原发性肉芽肿的这个区域缺氧，形态上与人类肺部病变的描述相似。因此，这些结果表明，这个无细胞边缘可能是持续存在的杆菌耐受药物治疗的主要位置。
