Temporal change in cytokine expression.

Rationale
Mycobacterium avium complex, is the most common nontuberculous mycobacterial respiratory pathogen in humans. Disease mechanisms are poorly understood due to the absence of a reliable animal model for M. avium complex pulmonary disease.
Objectives
The objectives of this study were to assess the susceptibility, immunologic and histopathologic responses of the common marmoset (Callithrix jacchus) to M. avium complex pulmonary infection.
Methods
7 adult female marmosets underwent endobronchial inoculation with 108 colony-forming units of M. intracellulare and were monitored for 30 or 60 days. Chest radiograph was assessed at baseline (prior to infection) and at the time of sacrifice (30 days for 3 animals and 60 days for 4 animals), and bronchoalveolar lavage cytokines, histopathology and cultures of the bronchoalveolar lavage, lungs, liver and kidney were assessed at time of sacrifice. Serum cytokines were monitored at baseline and weekly for 30 days for all animals and at 60 days for those alive. Group differences in serum cytokine measurements between those that tested positive versus negative for the M. intracellulare infection were assessed using a series of linear mixed models.
Measurements and main results
Five of seven animals (two at 30 days and three at 60 days of infection) had positive lung cultures for M. intracellulare. Extra-pulmonary cultures were positive in three animals. All animals appeared healthy throughout the study. All five animals with positive lung cultures had radiographic changes consistent with pneumonitis. At 30 days, those with M. intracellulare lung infection showed granulomatous inflammation, while at 60 days there were fewer inflammatory changes but bronchiectasis was noted. The cytokine response in the bronchoalveolar lavage fluid was uniformly greater in the animals with positive M. intracellulare cultures than those without a productive infection, with greater levels at 30-days compared to 60-days. Similarly, serum cytokines were more elevated in the animals that had positive M. intracellulare cultures compared to those without a productive infection, peaking 14–21 days after inoculation.
Conclusion
Endobronchial instillation of M. intracellulare resulted in pulmonary mycobacterial infection in marmosets with a differential immune response, radiographic and histopathologic abnormalities, and an indolent course consistent with M. avium complex lung infection in humans.

研究依据
鸟分枝杆菌复合群（Mycobacterium avium complex, MAC）是人类最常见的非结核分枝杆菌呼吸道致病菌。由于缺乏针对鸟分枝杆菌复合群肺部疾病的可靠动物模型，其致病机制至今仍未得到充分阐明。

研究目的
本研究旨在评估普通狨猴（Callithrix jacchus）对鸟分枝杆菌复合群肺部感染的易感性、免疫应答及组织病理学反应。

研究方法
7只成年雌性普通狨猴经支气管内接种10^8菌落形成单位（colony-forming units, CFU）的胞内分枝杆菌（Mycobacterium intracellulare），并分别监测30天或60天。于基线（感染前）及处死时对所有动物进行胸部影像学评估：其中3只动物于感染30天时处死，4只于感染60天时处死。处死时采集支气管肺泡灌洗液（bronchoalveolar lavage, BAL）进行细胞因子检测、组织病理学检查，并对支气管肺泡灌洗液、肺、肝及肾进行培养检测。所有动物于基线及接种后每周监测血清细胞因子水平至30天，存活至60天的动物亦于60天时进行检测。采用一系列线性混合模型，对胞内分枝杆菌感染检测阳性与阴性组的血清细胞因子水平差异进行统计分析。

检测方法与主要结果
7只动物中共有5只的肺部培养呈胞内分枝杆菌阳性（感染30天时2只，感染60天时3只），另有3只动物的肺外培养呈阳性。所有实验动物在研究全程均状态良好。肺部培养阳性的5只动物均出现符合肺炎的影像学改变。感染30天时，胞内分枝杆菌肺部感染动物可见肉芽肿性炎症；感染60天时，炎症反应有所减轻，但观察到支气管扩张病变。胞内分枝杆菌培养阳性动物的支气管肺泡灌洗液细胞因子反应均显著高于未出现有效感染的动物，且感染30天时的细胞因子水平高于60天时。类似地，胞内分枝杆菌培养阳性动物的血清细胞因子水平亦显著高于未出现有效感染的动物，且于接种后14~21天达到峰值。

研究结论
经支气管内接种胞内分枝杆菌可在狨猴体内引发肺部分枝杆菌感染，其免疫应答、影像学及组织病理学特征存在差异，且病程呈慢性迁延性，与人类鸟分枝杆菌复合群肺部感染的临床病程特征相符。