Development of a monkey model of Bordetella pertussis infection and disease

描述(申请人提供)：百日咳(百日咳)是由百日咳杆菌引起的呼吸道感染。这种疾病的最典型特征是持续数周甚至数月的阵发性(突然、猛烈、失控)咳嗽，使人虚弱。在婴儿中，百日咳可发展为致命的心肺衰竭，但百日咳是一种在所有年龄段的人中都能观察到的疾病。百日咳杆菌与呼吸道上皮结合并在其上繁殖，释放出几种被认为与病理有关的毒素。尽管对这种病原体的几种毒力因子的结构和功能有了详细的分子理解，但我们对这种感染和疾病的发病机制的了解仍然存在很大差距。特别是，我们对百日咳的病因及其特殊特征几乎一无所知。这主要是由于缺乏复制人类感染和疾病的已建立的动物模型。20世纪20年代和30年代关于灵长类动物实验性百日咳感染的研究取得了不同程度的成功，但有足够的积极结果值得进行新的现代研究。在这一应用中，我们建议探索使用非人类灵长类动物模型来研究百日咳感染和疾病的可行性。食蟹猴将被气管内接种百日咳杆菌，感染和疾病将随着时间的推移进行监测，包括评估任何引起咳嗽的情况。成功建立这个模型将使我们能够解决这个发病机制的一些方面，特别是咳嗽，这些方面以前没有经过实验研究，并将提供一个更相关的人类百日咳感染和疾病的模型。 与公共卫生相关：百日咳是唯一一种近年来呈上升趋势的疫苗可预防疾病，据报道，2005年美国的百日咳达到了50年来的最高水平。这种感染在婴儿中可能是致命的，并可能在其他人中导致虚弱和长期咳嗽，对这些人来说，没有有效的治疗方法。由于目前还不允许对百日咳进行人体志愿者实验，猴子可能是复制人类感染和疾病，特别是持续严重咳嗽的最佳动物模型。该模型的成功建立将使我们能够研究百日咳以及百日咳感染和疾病的许多其他方面，并可能导致新的治疗方法的发展，以预防或改善百日咳的严重咳嗽。

DESCRIPTION (provided by applicant): Pertussis (whooping cough) is caused by respiratory infection with the bacterial pathogen Bordetella pertussis. The disease is characterized most typically by debilitating episodes of paroxysmal (sudden, violent, uncontrolled) coughing that persist for weeks or even months. In young infants, pertussis can progress to fatal cardio-respiratory failure, but pertussis cough is a disease observed in individuals of all ages. B. pertussis binds to and multiplies on the respiratory epithelium, releasing several toxins that are thought to contribute to the pathology. Despite a detailed molecular understanding of the structure and function of several virulence factors of this pathogen, there remain significant gaps in our knowledge of the pathogenesis of this infection and disease. In particular, we know next to nothing about the cause of pertussis cough and its peculiar characteristics. This is due primarily to the lack of an established animal model that reproduces the infection and disease seen in humans. Studies in the 1920s and 1930s on experimental pertussis infections in primates met with variable success, but there were sufficient positive results to warrant a new and modern investigation. In this application, we propose to explore the feasibility of using a non-human primate model to study pertussis infection and disease. Cynomolgus monkeys will be inoculated intratracheally with B. pertussis and infection and disease will be monitored over time, including assessment of any coughing elicited. Success in establishing this model would allow us to address aspects of this pathogenesis, particularly the cough, that have not previously been amenable to experimental study, and would provide a more relevant model of human pertussis infection and disease. PUBLIC HEALTH RELEVANCE: Pertussis is the only vaccine-preventable disease that is on the rise in recent years, with 50-year highs reported in the US in 2005. The infection can be fatal in infants and can cause a debilitating and prolonged cough in other individuals, for whom there is no effective treatment. Since human volunteer experiments are not currently permissible for pertussis, monkeys potentially represent the best animal model that reproduces the infection and disease seen in humans, particularly the prolonged severe cough. Successful establishment of this model will allow us to study pertussis cough, as well as many other aspects of the infection and disease, and may lead to the development of novel therapeutics to prevent or ameliorate the severe cough in pertussis.