Lethal Mycobacterium bovis Bacillus Calmette Guerin infection in nitric oxide synthase 2-deficient mice: Cell-mediated immunity requires nitric oxide synthase 2
Lethal Mycobacterium bovis Bacillus Calmette Guerin infection in nitric oxide synthase 2-deficient mice: Cell-mediated immunity requires nitric oxide synthase 2
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DOI：
10.1038/labinvest.3780146
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发表时间：
2000-09-01
影响因子：
5
通讯作者：
Ryffel, B
中科院分区：
文献类型：
--
作者：
Garcia, I;Guler, R;Ryffel, B
利用一氧化氮合酶2(NOS2)缺陷小鼠研究一氧化氮(NO)在牛分枝杆菌卡介苗(BCG)感染中的作用。我们证明NOS2缺陷小鼠无法清除卡介苗，并在8到12周内死于卡介苗感染(10(6)CFU)并伴有恶病质和肺炎，而所有感染的野生型小鼠都存活下来。分枝杆菌载量以肺、脾最多。NOS2基因缺陷的小鼠出现了由巨噬细胞和活化的T细胞组成的大肉芽肿，以及脾中的干酪性坏死性病变。NOS2缺陷小鼠肉芽肿中的巨噬细胞酸性磷酸酶活性降低，提示巨噬细胞激活需要NO。NOS2的缺失影响了Th1型免疫反应的细胞因子的产生，但IL-18除外。与野生型小鼠相比，小鼠血清IL-12p40水平升高，干扰素-γ水平降低。在整个感染期间观察到，NOS2的缺乏导致了肿瘤坏死因子的过量产生。此外，与野生型小鼠相比，TNFR1和TNFR2的脱落也发生了改变。上调肿瘤坏死因子可能是对NOS2缺失的一种补偿。可溶性肿瘤坏死因子受体的晚期中和导致NOS2缺陷小鼠病情加重和加速死亡，但对野生型小鼠没有影响。总而言之，NOS2缺陷小鼠不能杀死牛卡介苗分枝杆菌，导致分枝杆菌堆积，免疫系统急剧激活，促炎细胞因子过度产生，导致死亡。
The role of nitric oxide (NO) in Mycobacterium bovis Bacillus Calmette Guerin (BCG) infection was investigated using nitric oxide synthase 2 (nos2)-deficient mice, because NO plays a pivotal protective role in M. tuberculosis infection. We demonstrate that nos2-deficient mice were unable to eliminate BCG and succumbed within 8 to 12 weeks to BCG infection (10(6) CFU) with cachexia and pneumonia, whereas all infected wild-type mice survived. The greatest mycobacterial loads were observed in lung and spleen. Nos2-deficient mice developed large granulomas consisting of macrophages and activated T cells and caseous necrotic lesions in spleen. The macrophages in granulomas from nos2-deficient mice had reduced acid phosphatase activities, suggesting that NO is required for macrophage activation. The absence of NOS2 affected the cytokine production of the Th1 type of immune response, except IL-18. Serum amounts of IL-12p40 were increased and IFN-gamma was decreased compared with wild-type mice. The lack of NOS2 resulted in an overproduction of TNF, observed throughout the infection period. Additionally, TNFR1 and TNFR2 shedding was altered compared with wild-type mice. Up-regulation of TNF may be compensatory for the lack of NOS2. The late neutralization of TNF by soluble TNF receptors resulted in heightened disease severity and accelerated death in nos2-deficient mice but had no effect in wild-type mice. In conclusion, the inability of nos2-deficient mice to kill M. bovis BCG resulted in an accumulation of mycobacteria with a dramatic activation of the immune system and overproduction of pro-inflammatory cytokines, which resulted in death.