Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-α/β
Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-α/β
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DOI：
10.1073/pnas.091096998
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发表时间：
2001-05-08
影响因子：
11.1
通讯作者：
Kaplan, G
中科院分区：
文献类型：
--
作者：
Manca, C;Tsenova, L;Kaplan, G
为了了解毒力分枝杆菌如何破坏宿主免疫并建立疾病，我们检查了小鼠对各种人类爆发结核分枝杆菌临床分离株感染的不同反应。一个临床分离株，HN 878，被发现是高毒力，证明了异常早期死亡的感染免疫能力强的小鼠，与其他临床分离株感染。对存活率的不同影响需要淋巴细胞功能，因为感染HN 878或其他临床分离株的严重联合免疫缺陷（SCID）小鼠的死亡率相同。HN 878的高毒力与其不能诱导M.来自感染小鼠的脾和淋巴结细胞的结核特异性增殖和IFN-γ产生。此外，在HN 878感染小鼠的肺中观察到肿瘤坏死因子-cu（TNF-α）、IL-6、IL-12和IFN-γ mRNA水平降低2- 4倍。IL-10、IL-4和IL-5 mRNA水平在HN 878感染小鼠的肺中没有显著升高。相反，IFN-α mRNA水平在这些小鼠的肺中显著更高。为了进一步研究1型IFN的作用，用纯化的IFN-α/β鼻内处理感染HN 878的小鼠。治疗导致肺细菌负荷增加，甚至进一步降低生存率。这些结果表明，HN 878的超强毒力可能是由于该菌株不能刺激Th 1型免疫。此外，缺乏对HN 878应答的Th 1免疫的发展似乎与1型IFN的诱导增加有关。
To understand how Virulent mycobacteria subvert host immunity and establish disease, we examined the differential response of mice to infection with various human outbreak Mycobacterium tuberculosis clinical isolates. One clinical isolate, HN878, was found to be hypervirulent, as demonstrated by unusually early death of infected immune-competent mice, compared with infection with other clinical isolates. The differential effect on survival required lymphocyte function because severe combined immunodeficiency (SCID) mice infected with HN878 or other clinical isolates all died at the same rate. The hypervirulence of HN878 was associated with failure to induce M. tubercolosis-specific proliferation and lFN-gamma production by spleen and lymph node cells from infected mice. In addition, 2- to 4-fold lower levels of tumor necrosis factor-cu (TNF-alpha), IL-6, IL-12, and IFN-gamma mRNAs were observed in lungs of HN878-infected mice. IL-10, IL-4, and IL-5 mRNA levels were not significantly elevated in lungs of HN878 infected mice. In contrast, IFN-a mRNA levels were significantly higher in lungs of these mice. To further investigate the role of Type 1 IFNs, mice infected with HN878 were treated intranasally with purified IFN-alpha/beta. The treatment resulted in increased lung bacillary loads and even further reduced survival. These results suggest that the hypervirulence of HN878 may be due to failure of this strain to stimulate Th1 type immunity. In addition, the lack of development of Th1 immunity in response to HN878 appears to be associated with increased induction of Type 1 IFNs.