Disease dynamics of campylobacteriosis in the ferret model

 描述（申请人提供）：空肠弯曲菌是美国食源性人类胃肠炎的主要原因，发病率为每100，000人中13.6例确诊病例，但预计发病率要高得多，估计美国每年约有130万例弯曲菌病，主要来自家禽，它是C.空肠。弯曲杆菌病的特征是感染后2至5天出现轻度至重度的血性腹泻、腹痛和发热，但也可导致格林-巴利综合征（GBS），这是一种由免疫系统攻击外周神经系统引起的麻痹性疾病。研究揭示C.由于缺乏复制人类疾病临床特征的动物模型，导致人类弯曲杆菌病发展的空肠受到阻碍。广泛使用的鸡模型不是疾病模型，因为鸡是弯曲杆菌属物种的天然宿主。模拟人类疾病的动物模型的开发集中在免疫缺陷小鼠上，包括MyD 88，IL-10或NF-kB突变体，或更复杂的实验，其中在抗生素治疗后用人类肠道微生物群取代鼠肠道微生物群。这些是人类疾病的较差模型，因为定殖不会导致与人类感染一致的临床体征，或者因为定殖导致长期持续感染，也不同于在人类中观察到的感染。相比之下，幼雪貂的感染与人类感染非常相似，包括出血性腹泻的发展和再次感染后对疾病的抵抗。然而，对雪貂模型中弯曲杆菌病的宿主和微生物机制知之甚少。对于这个探索性的建议，一个广泛的方法来揭示生理和遗传因素有助于C。结合转录组学、遗传学、宏基因组学和代谢组学，将研究雪貂的空肠感染。这种方法已经成功地揭示了关于C的重要知识。研究发现了鸡胃肠道中的空肠寄生虫，包括发现了定植决定因子、新的调控元件和潜在的非编码小RNA。采用这一系统策略来研究疾病模型，随后对鸡腹泻结果进行比较分析，将为与C.空肠致病性该提案的拟议工作有以下两个目标：具体目标1。识别C。空肠致病性决定因素和相关因素 在雪貂模型中使用转录组学和全基因组诱变研究-将在鸡模型中检查雪貂中鉴定为致病性关键的基因，以评估它们在无炎症和致病性迹象的肠道定殖中的作用。使用转录组学、宏基因组学和代谢组学研究确定雪貂对空肠弯曲菌感染的反应。

 DESCRIPTION (provided by applicant): Campylobacter jejuni is a leading cause of foodborne human gastroenteritis in the United States, with an incidence rate of 13.6 diagnosed cases per 100,000 individuals, though it is predicted that the incidence is much higher, with estimates of approximately 1.3 million cases of campylobacteriosis in the United States annually, arising primarily from poultry, which serves as a natural reservoir for C. jejuni. Campylobacteriosis is characterized by mild to severe, bloody diarrhea, abdominal pain, and fever occurring two to five days following infection, but can also lead to Guillain-Barré syndrome (GBS), a paralytic illness resulting from the immune system attack on the peripheral nervous system. Research to uncover factors of C. jejuni that contribute to development of human campylobacteriosis has been hindered by lack of an animal model that replicates the clinical features of human disease. The widely used chicken model is not a disease model, as chickens are a natural reservoir for Campylobacter species. Development of animal models that mimic human disease has centered on immunodeficient mice, including MyD88, IL-10 or NF-kB mutants, or more complex experiments where the murine gut microbiota is replaced with a human gut microbiota after antibiotic treatment. These are poor models of human disease as colonization does not result in clinical signs consistent with human infection, or because colonization leads to a long-term, persistent infection, also unlike what is observed in humans. In contrast, infection in young ferrets closely mimic human infection, including development of bloody diarrhea and resistance to disease upon re-infection. Little is understood, however, about host and microbial mechanisms that underlie campylobacteriosis in the ferret model. For this exploratory proposal, a broad approach to uncover physiological and genetic factors contributing to C. jejuni infection in ferrets will be taken, combining transcriptomics, genetics, metagenomics, and metabolomics. This approach has been successful at uncovering significant knowledge regarding C. jejuni commensalism in the chicken gastrointestinal tract, including the discovery of colonization determinants, new regulatory elements and potential non-coding small RNAs. Adopting this systems strategy to study a disease model, with subsequent comparative analysis of the chicken commensal findings, will provide unprecedented insight into important host-pathogen interactions relevant to C. jejuni pathogenicity. The proposed work for this proposal has the following two aims: Specific aim 1. Identify C. jejuni determinants and correlates of pathogenicity in the ferret model using transcriptomic and genome-wide mutagenesis studies -genes identified as critical for pathogenicity in the ferret will be examined in a chicken model to assess their rol in commensal colonization without inflammation and pathogenicity signs Specific aim 2. Determine the ferret response to Campylobacter jejuni infection using transcriptomic, metagenomic, and metabolomic studies.