Iron-cofactored superoxide dismutase inhibits host responses to Mycobacterium tuberculosis
Iron-cofactored superoxide dismutase inhibits host responses to Mycobacterium tuberculosis
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DOI：
10.1164/ajrccm.164.12.2106093
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发表时间：
2001-12-15
影响因子：
24.7
通讯作者：
Kernodle, DS
中科院分区：
文献类型：
--
作者：
Edwards, KM;Cynamon, MH;Kernodle, DS
超氧化物歧化酶（SOD）是需氧生物中普遍存在的一种金属酶，它催化超氧阴离子转化为过氧化氢。结核分枝杆菌的特殊之处在于它会分泌大量含铁辅因子的SOD。为了确定SOD在发病机制中的作用，我们构建了结核分枝杆菌H37Rv的SOD产量降低的突变体。与对照相比，SOD减少的分离株对过氧化氢的杀伤更敏感。这些分离株的毒力明显减弱，在静脉接种C57BL/6小鼠4周后，其在肺和脾脏中的细菌数量比有毒力的对照菌株少近100,000倍。在肺部，SOD减弱的结核分枝杆菌在24小时内诱导了强烈的间质单核细胞浸润，并且通过TUNEL染色发现许多细胞发生凋亡，而有毒力的H37Rv表现出极轻微的早期炎症反应，且只有极少数间质单核细胞凋亡。在长期感染过程中，C57BL/6小鼠对SOD减弱的结核分枝杆菌的耐受性优于卡介苗，体重增加多68%，从脾脏中清除细菌更快，肺泡肺浸润更少。这些结果确立了SOD在结核病发病机制中的重要性。其作用似乎部分是通过抑制宿主的天然免疫反应来介导的，包括感染组织的早期单核细胞浸润和细胞凋亡。
Superoxide dismutase (SOD) is a ubiquitous metalloenzyme in aerobic organisms that catalyzes the conversion of superoxide anion to hydrogen peroxide. Mycobacterium tuberculosis is unusual in that it secretes large quantities of iron-cofactored SOD. To determine the role of SOD in pathogenesis, we constructed mutants of M. tuberculosis H37Rv with reduced SOD production. Compared with controls, SOD-diminished isolates were more susceptible to killing by hydrogen peroxide. The isolates were markedly attenuated, exhibiting nearly 100,000-fold fewer bacilli than virulent control strains in the lungs and spleens of C57BL/6 mice 4 wk after intravenous inoculation. In the lung, SOD-attenuated M. tuberculosis induced robust interstitial mononuclear cell infiltration within 24 In and many cells were apoptotic by TUNEL staining, whereas virulent H37Rv exhibited minimal early inflammatory response and only rare interstitial mononuclear cell apoptosis. During prolonged infections, C57BL/6 mice tolerated SOD-attenuated M. tuberculosis better than BCG, exhibiting 68% greater weight gain, quicker eradication of bacilli from the spleen, and less alveolar lung infiltration. These results establish the importance of SOD in the pathogenesis of tuberculosis. Its effect appears to be mediated in part by inhibiting innate host immune responses, including early mononuclear cell infiltration of infected tissues and apoptosis.