Disease dynamics of campylobacteriosis in the ferret model

雪貂模型中弯曲菌病的疾病动态

基本信息

批准号：
8966005
负责人：
Victor J. DiRita
金额：
$ 18.84万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8966005
关键词：
Abdominal Pain Adopted Animal Model Animals Antibiotic Therapy Behavior Blood Campylobacter Campylobacter infection Campylobacter jejuni Chickens Clinical Complex DNA Insertion Elements Data Development Diagnosis Diarrhea Disease Disease Resistance Disease model Domestic Fowls Ferrets Fever Gastroenteritis Gastrointestinal tract structure Genes Genetic Genomics Guillain-Barré Syndrome Health Hemorrhagic colitis Human Immune Immune system Immunocompetent Immunocompromised Host Immunodeficient Mouse Incidence Individual Infection Inflammation Interleukin-10 Knowledge Lead Metagenomics Modeling Mus Mutagenesis NF-kappa B Output Paralysed Pathogenicity Peripheral Nervous System Physiological Population Regulatory Element Research Role Small RNA Stomach Symbiosis Syndrome System Therapeutic United States Untranslated RNA Work animal model development base comparative factor C foodborne genome-wide gut microbiota human disease insight metabolomics microbial host mouse model mutant pathogen prophylactic research study response targeted treatment transcriptomics

项目摘要

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.

描述（由适用提供）：美国野生动物的人类胃肠炎是美国的主要原因，事件发生率为13.6例，每10万人诊断为诊断案件，尽管预计该事件要高得多，估计估计是130万病例，大约有130万病例，大约有130万病例的野生动物病例，因为在美国，pationje at persy a sers a as a is a as as a ins a per a ins a as a ins a rece as a c. are a c. are a c. res a。弯曲杆菌的特征是在感染后两到五天发生轻度至重度，血液腹泻，腹痛和发烧，但也可能导致Guillain-Barré综合征（GBS），这是由免疫系统对周围神经系统的攻击引起的麻痹疾病。缺乏复制人类疾病的临床特征的动物模型，阻碍了发现有助于人类弯曲杆菌发展的空肠梭菌因素的研究。广泛使用的鸡模型不是疾病模型，因为鸡是弯曲杆菌物种的天然晶状体。模仿人类疾病的动物模型的开发已集中在免疫缺陷的小鼠上，包括MyD88，IL-10或NF-KB突变体，或更复杂的实验，在这些实验中，在抗生素治疗后，鼠肠肠菌被鼠肠肠菌菌体被人类肠道菌群代替。这些是人类疾病的贫困模型，因为定植并不能导致与人类感染一致的临床迹象，或者因为定植会导致长期，持续感染，这也与人类观察到的不同。相反，年轻雪貂的感染紧密模仿了人类感染，包括血液腹泻的发展和对疾病的抗性。然而，几乎没有什么知识是关于在雪貂模型中弯曲杆菌病的宿主和微生物机制。对于这一探索性建议，将采取一种广泛的方法，用于揭示有助于雪貂感染的身体和遗传因素，结合转录组学，遗传学，宏基因组学和代谢组学。这种方法已经成功地揭示了有关鸡胃肠道中的空肠梭菌的重要知识，包括发现定殖确定剂，新的调节元素和潜在的非编码小RNA。采用这种系统策略研究疾病模型，随后对鸡肉共同发现的比较分析将提供对与旋转梭菌致病性相关的重要宿主 - 病原体相互作用的前所未有的见解。该提案的拟议工作具有以下两个目的：特定目的1。确定旋转氏菌确定致病性和相关性在使用转录组和全基因组诱变研究的雪貂模型中，将在鸡模型中检查被确定为对雪貂致病性至关重要的基因，以评估其在共生定植中的ROL，而无需炎症和致病性迹象特定的目标。