Genetic adaptation in Campylobacter: mechanisms and impacts on human health

描述(申请人提供)：食源性空肠弯曲菌(CJ)每年导致250万至300万人患病，约100人死亡，估计成本在16亿至62亿美元之间。家禽是空肠弯曲菌引起的人类疾病的主要宿主。我们的长期目标是通过在两个领域制定有效的控制战略来预防人类疾病：a)生物控制剂，以减少家禽的病源发展；b)增强先天或获得性免疫，以减少人类的定居。此前，我们证明了所有CJ菌株都分析了在Ross 308肉鸡上的定植，而这些菌株中只有一小部分在我们的人类疾病模型C57BL/6J IL10(-/-)小鼠上定植。在定居期间，CJ遗传多样性在肉鸡GI区扩大，而在小鼠GI区遗传多样性严重减少。我们还证明了这两种不同的遗传适应方法促进了CJ随后对小鼠的定植。我们的中心假设是，家禽的遗传适应在CJ随后在小鼠身上定植和致病的能力中起着关键作用。为了解决这一假设，我们将实现以下具体目标：1)通过分析偶发基因突变的频率和模式，研究肉鸡和小鼠遗传多样性的产生机制；2)阻断肉鸡的遗传适应，并分析其对随后在小鼠身上定植和致病能力的影响。了解家禽中CJ人类疾病宿主的发展将对与这种食源性病原体相关的人类疾病产生重大的积极影响。与公共卫生相关：食源性空肠弯曲菌(CJ)每年导致250万至300万人患病和约100人死亡，估计成本在16亿至62亿美元之间。家禽是空肠弯曲菌引起的人类疾病的主要宿主。我们的长期目标是通过在两个领域制定有效的控制战略来预防人类疾病：a)生物控制剂，以减少家禽的病源发展；b)增强先天或获得性免疫，以减少人类的定居。

DESCRIPTION (provided by applicant): The food borne pathogen Campylobacter jejuni (CJ) causes between 2.5 and 3 million human disease cases and approximately 100 deaths annually at an estimated cost of between 1.6 and 6.2 billion dollars. Poultry is the major reservoir for human disease caused by CJ. Our long term goal is to prevent human illness by developing effective control strategies in two areas: a) bio-control agents to reduce disease reservoir development in poultry; b) enhance innate or adaptive immunity to reduce human colonization. Previously we demonstrated that all CJ strains analyzed colonize Ross 308 broilers while only a small number of these strains colonize C57BL/6J IL10 (-/-) mice, our model for human disease. During colonization, CJ genetic diversity expands in the broiler GI tract while genetic diversity is severely reduced in the mouse GI tract. We also demonstrated that these two dissimilar methods of genetic adaptation promote subsequent colonization of mice by CJ. Our central hypothesis is that genetic adaptation in poultry plays a key role in the ability of CJ subsequently to colonize and cause disease in mice. To address this hypothesis, we will accomplish the following Specific Aims: 1) study the mechanisms for generating genetic diversity in broilers and mice by analyzing the frequency and pattern of mutation in contingency genes; 2) block genetic adaptation in broilers and analyze the impact on subsequent ability to colonize and cause disease in mice. An understanding of CJ human disease reservoir development in poultry will result in a major positive impact on human illness associated with this food borne pathogen. PUBLIC HEALTH RELEVANCE: The food borne pathogen Campylobacter jejuni (CJ) causes between 2.5 and 3 million human disease cases and approximately 100 deaths annually at an estimated cost of between 1.6 and 6.2 billion dollars. Poultry is the major reservoir for human disease caused by CJ. Our long term goal is to prevent human illness by developing effective control strategies in two areas: a) bio-control agents to reduce disease reservoir development in poultry; b) enhance innate or adaptive immunity to reduce human colonization.