Development of a monkey model of Bordetella pertussis infection and disease

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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.