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Study of virulence and drug-susceptabiltly of MAC strains isolated from Japanese patients with the nodular-bronchiectasis type MAC disease

日本结节性支气管扩张型 MAC 病患者 MAC 菌株毒力及药敏研究

基本信息

批准号：
18590850
负责人：
TOMIOKA Haruaki
金额：
$ 2.53万
依托单位：
Shimane University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590850/
关键词：
Mycobacterium salute complex MAC lung disease nodular-hronchiectasis type 感染症 MAC MAC感染症

项目摘要

There are recently observed increasing cases of Mycobacterium avium complex (MAC) lung disease in patients with no apparent risk factors, such as upper lobe cavitary disease in the male with a history of alcohol and heavy cigarette abuse. The patients are primarily elderly women with no history of smoking, and reticulonodular infiltrates and have patchy bilateral bronchiectasis, with routine involvement of the right middle lobe and lingula. This nodular-bronchiectasis (NB) type MAC pulmonary infection is currently increasing in Japan. Although the risk factors for such MAC diseases are primarily attributable to host-side conditions, such as severe exposure to MAC pathogens in persons frequently taking shower bath and the peculiarity in the anatomical structure and physiological function of woman's lungs. At present, it is unclear whether or not there are MAC populations which preferentially cause nodular-bronchiectasis (NB) type MAC lung disease rather than causing MAC disease that mim … More ics tuberculosis (TB) with upper lobe cavitary disease frequently encountered in the male, called as TB type MAC disease. Here, we examined profiles of virulence and drug-susceptibiltiy of MAC strains isolated from Japanese patients with the NB type MAC disease (NB-MAC) and compared with the case of MAC isolates from Japanese patients with the TB type MAC disease (TB-MAC). Five each strains of NB-MAC and TB-MAC were compared with each other group for their invasiveness and the ability to intracellularly replicate in various types of cultured cells of human origin, including three macrophage cell lines and one alveolar and one bronchial epithelial cell lines. The following findings were obtained. (1) Within human macrophage cell lines, such as THP-1 and MM6 macrophages, NB-MAC strains replicated more rapidly when compared to TB-MAC strains, although such difference is insignificant. (2) There was observed no difference between NB-MAC and TB-MAC for the rate of intracellular growth within the U937 murine macrophage cell line. (3) Inside in the A549 human type II alveolar epithelial cell line, the intracellular growth of NB-MAC strains was somewhat more vigorous than TB-MAC strains. (4) Both NB-MAC and TB-MAC strains showed similar abilities to internalize into NL20 human bronchial epithelial cell line and intracellularly replicate within the NL20 cells. (5) In extracellular milieus such as those in 7HSF medium, NB-MAC grew more rapidly than TB-MAC. (6) Both NB- and TB-MAC strains induced reactive oxygen intermediate and reactive nitrogen intermediate production by THP-1 macrophages after bacterial internalization. These two types of MAC organisms showed the same efficacies in inducing macrophage generation of these antimicrobial effector molecules. (7) Drug susceptibilities of NB- and TB-MAC strains to some antimycobacterial drugs, such as rifampicin (RFP), fluoroquinolones and isoniazid (INH) were considerably different from each other, as follows. On the basis of MIC_<60>, NB-MAC was about four-times less susceptible to RFP, and fluoroquinolones (levofloxacin, gatifloxacin, sitafloxacin) than TB-MAC, while the former was two-times more susceptible to INH than the latter MAC strains. Both the two MAC showed the same levels of susceptibility to the other test drugs, including macrolides (clarithromycin, azithromycin), rifabutin, ethambutol and aminoglycosides (streptomycin, amikacin). The present findings indicate the following. First, there may be no essential difference in virulence on the basis of infectivity to host macrophages and lung epithelial cells between MAC strains isolated from NB-MAC disease and those from TB-MAC disease. Second, There may be some levels of difference in drug susceptibility for these two types of MAC isolates, especially in cases of RFP, fluoroquinolones and INH, thereby suggesting the possibility that clinical output of treatment of MAC patients using these drugs may differ from patients with NB type disease to those with TB type one. Less

最近观察到，在没有明显危险因素的患者中，如有酗酒和重度吸烟史的男性上肺叶空洞病，禽分枝杆菌复合体（MAC）肺病的病例增加。患者主要为无吸烟史的老年妇女，网状结节浸润和双侧片状支气管扩张，常规累及右中叶和舌部。结节性支气管扩张（NB）型MAC肺部感染目前在日本呈上升趋势。尽管此类MAC疾病的风险因素主要可归因于宿主侧条件，例如经常淋浴的人严重暴露于MAC病原体以及女性肺部解剖结构和生理功能的特殊性。目前尚不清楚是否存在更容易引起结节性支气管扩张（NB）型MAC肺病的MAC人群，而不是引起男性常见的伴有上肺叶空洞病的MAC肺病，称为TB型MAC病。在这里，我们检测了从日本NB型MAC患者（NB-MAC）分离的MAC菌株的毒力和药物敏感性，并与从日本TB型MAC患者（TB-MAC）分离的MAC菌株进行了比较。比较NB-MAC和TB-MAC各5株菌株在3株巨噬细胞系、1株肺泡上皮细胞系和1株支气管上皮细胞系中侵袭性和细胞内复制能力。研究结果如下：(1)在THP-1和MM6等人巨噬细胞系中，NB-MAC株的复制速度比TB-MAC株快，但差异不显著。(2) NB-MAC与TB-MAC对小鼠U937巨噬细胞胞内生长速率无显著差异。(3)在A549人II型肺泡上皮细胞系内，NB-MAC菌株的细胞内生长比TB-MAC菌株稍强。(4) NB-MAC和TB-MAC菌株均能在NL20人支气管上皮细胞系中内化并在NL20细胞内复制。(5)在7HSF等细胞外环境中，NB-MAC比TB-MAC生长更快。(6) NB-和TB-MAC菌株内化后均诱导THP-1巨噬细胞产生活性氧中间体和活性氮中间体。这两种类型的MAC生物在诱导巨噬细胞产生这些抗菌效应分子方面表现出相同的功效。(7) NB-和TB-MAC菌株对利福平（RFP）、氟喹诺酮类药物和异烟肼（INH）等抗菌药物的敏感性差异较大，表现为：在MIC_<60>的基础上，NB-MAC对RFP、氟喹诺酮类药物（左氧氟沙星、加替沙星、西他沙星）的敏感性约为TB-MAC的4倍，对INH的敏感性为TB-MAC的2倍。两种MAC对其他试验药物的敏感性水平相同，包括大环内酯类药物（克拉霉素、阿奇霉素）、利福布汀、乙胺丁醇和氨基糖苷类药物（链霉素、阿米卡星）。目前的调查结果表明：首先，基于对宿主巨噬细胞和肺上皮细胞的感染性，NB-MAC病分离的MAC菌株与TB-MAC病分离的MAC菌株在毒力上可能没有本质差异。第二，这两种类型的MAC分离株可能存在一定程度的药敏差异，特别是在RFP、氟喹诺酮类药物和INH的病例中，这表明使用这些药物治疗MAC患者的临床输出可能不同于NB型疾病患者和TB 1型疾病患者。少