Disease dynamics of campylobacteriosis in the ferret model

雪貂模型中弯曲菌病的疾病动态

• 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
• 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

 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(申请人提供)：空肠弯曲杆菌是美国食源性人类胃肠炎的主要病因，每10万人中有13.6例确诊病例，尽管预测发病率要高得多，估计美国每年约有130万例弯曲杆菌病，主要由家禽引起，家禽是空肠弯曲杆菌的天然宿主。弯曲杆菌病的特征是感染后两到五天出现轻度到重度的血性腹泻、腹痛和发烧，但也可能导致格林-巴利综合征(GBS)，这是一种由免疫系统对周围神经系统的攻击引起的瘫痪疾病。由于缺乏复制人类疾病临床特征的动物模型，揭示空肠弯曲杆菌导致人类弯曲杆菌病发展的因素的研究一直受到阻碍。广泛使用的鸡模型不是疾病模型，因为鸡是弯曲杆菌物种的天然储存库。模拟人类疾病的动物模型的开发主要集中在免疫缺陷小鼠身上，包括MyD88、IL-10或NF-kB突变体，或者更复杂的实验，即在抗生素治疗后用人类肠道微生物群取代小鼠的肠道微生物群。这些都是人类疾病的糟糕模型，因为殖民不会导致与人类感染相一致的临床症状，或者因为殖民导致长期、持续的感染，也不像在人类中观察到的那样。相比之下，幼年雪貂的感染与人类感染非常相似，包括发生血性腹泻和再次感染时对疾病的抵抗力。然而，人们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，将采取广泛的方法来揭示导致雪貂空肠弯曲菌感染的生理和遗传因素，结合转录组学、遗传学、元基因组学和代谢组学。这种方法已经成功地揭示了关于空肠弯曲菌在鸡胃肠道共生的重要知识，包括发现了定植决定因素、新的调控元件和潜在的非编码小RNA。采用这种系统策略来研究疾病模型，并随后对鸡的共生结果进行比较分析，将为研究与空肠弯曲菌致病性相关的重要宿主-病原体相互作用提供前所未有的见解。这项提案的拟议工作有以下两个目标：具体目标1.确定空肠弯曲菌致病性的决定因素和相关性 在利用转录和全基因组突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至关重要的基因，以评估它们在没有炎症和致病迹象的共生定植中的作用2.使用转录学、后基因组和代谢组学研究来确定雪貂对空肠弯曲杆菌感染的反应。

项目成果

Phosphate Transporter PstSCAB of Campylobacter jejuni Is a Critical Determinant of Lactate-Dependent Growth and Colonization in Chickens.

空肠弯曲菌的磷酸转运蛋白 PstSCAB 是鸡中乳酸依赖性生长和定植的关键决定因素。

• DOI: 10.1128/jb.00716-19
• 发表时间: 2020
• 期刊: Journal of bacteriology
• 影响因子: 3.2
• 作者: Sinha,Ritam;LeVeque,RhiannonM;Bowlin,MarvinQ;Gray,MichaelJ;DiRita,VictorJ
• 通讯作者: DiRita,VictorJ