Diet driven evolution of epidemic ribotypes of Clostridium difficile

饮食驱动艰难梭菌流行性核糖型的进化

• 批准号: 10053311
• 负责人: ROBERT A BRITTON
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-17 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053311
• 关键词: Acids; Address; Affinity; Amino Acid Substitution; Animal Feed; Animals; Antibiotics; Attenuated; Back; Biochemistry; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clostridium difficile; Communities; Complex; Data; Diet; Disaccharides; Disease; Disease Outbreaks; Disease Outcome; Enzymes; Epidemic; Europe; Evolution; Family suidae; Food; Food Additives; Food Supplements; Food Supply; Genes; Genetic; Genome; Glucose; Grant; Growth; Health Care Costs; High Prevalence; Hospitals; Human; Ice Cream; Infection; Intestines; Inulin; Invaded; Journals; Knock-out; Label; Laboratories; Link; Livestock; Medicine; Metabolism; Modeling; Morbidity - disease rate; Nature; New England; Nosocomial Infections; Operon; Pathogenesis; Phosphotransferases; Phylogenetic Analysis; Physiology; Polysaccharides; Production; Property; Proteins; Public Health; Regulation; Reporting; Research; Ribotypes; Role; Severity of illness; Shellfish; Single Nucleotide Polymorphism; Starch; Sucrose; Toxin; Trehalose; United States; Work; antibiotic-associated diarrhea; arabinogalactan; base; beef; cost; dietary; emerging pathogen; enteric infection; fitness; fluoroquinolone resistance; improved; innovation; microbiota; mortality; mouse model; mutant; pathogen; sugar; transmission process

The emergence of pathogens that cause increased morbidity and mortality is a major public health concern. Clostridium difficile is a major cause of hospital acquired infection and is the leading cause of antibiotic-associated diarrhea. In the past decade, two epidemic ribotypes (RT027 and RT078) of C. difficile have emerged as major ribotypes in hospital outbreaks around the world despite not being observed at significant levels prior to the year 2000. These ribotypes are associated with increased morbidity and mortality and have been classified as hypervirulent. However, the mechanistic basis for why these strains began to emerge in the early 2000s is unclear. We have found that RT027 and RT078 strains have acquired the ability to grow on the disaccharide trehalose more efficiently than other ribotypes of C. difficile. Our preliminary data shows that the mechanistic bases for the improved growth in these two ribotypes are genetically and mechanistically distinct, suggesting convergent evolution of improved trehalose metabolism in these phylogenetically distinct ribotypes. In addition, we have found that disrupting the ability of a RT027 strain to utilize trehalose dramatically attenuates disease severity, suggesting that trehalose metabolism contributes to the hypervirulent nature of RT027 and RT078 strains. Trehalose, a disaccharide of glucose, became a widely used food supplement after being granted GRAS status approval by the FDA in 2000 and EFSA in Europe in 2001. Trehalose has a number of desirable properties as a sugar additive due to the alpha, alpha 1-1 linkage that is heat and acid stable, which renders it 45% less sweet than sucrose. Normally found in foods such as mushrooms and shellfish, trehalose is now added to numerous food and drink products ranging from ground beef to ice cream. The addition of trehalose to the worldwide food supply coincides with the first reports of RT027 and RT078 strains in the early 2000s, even though these ribotypes were present in hospitals as far back as 1985. We propose that addition of increased levels of trehalose to the food supply has selected for RT027 and RT078 strains due to their ability to more efficiently metabolize trehalose and has contributed to hospital epidemics. We will use two recently developed models in our laboratory, human fecal minibioreactor array model of C. difficile invasion and a humanized microbiota mouse model of C. difficile infection, to study the impact of trehalose and improved trehalose metabolism on the ability of RT027 and RT078 strains to cause C. difficile infection. We will also investigate the mechanistic bases for improved trehalose metabolism of RT027 and RT078 strains. Finally, we will assess what impact improved trehalose metabolism has on colonization dynamics, disease severity and carriage in animals of these hypervirulent C. difficile ribotypes. The following specific aims are proposed: Aim 1. Investigate the mechanism of how trehalose metabolism by C. difficile increases disease severity. Aim 2. Understand the mechanistic basis for improved trehalose metabolism in RT027 C. difficile. Aim 3. Understand the role of the acquired trehalose operon on RT078 fitness and animal carriage. We expect this work will establish a link between the recent addition of trehalose in the human diet and the emergence of epidemic C. difficile ribotypes. This will provide the first direct evidence of the alteration of the human diet directly impacting the pathogenesis of an enteric infection.

导致发病率和死亡率增加的病原体的出现是主要的公共卫生 忧虑。艰难梭菌是医院后感染的主要原因，是 抗生素相关的腹泻。在过去的十年中，艰难梭菌两种流行病核糖型（RT027和RT078） 尽管未在 2000年之前的显着水平。这些结构型与发病率和死亡率的增加有关 并已被归类为高呼吸。但是，这些菌株为什么开始的机械基础 在2000年代初期出现尚不清楚。 我们发现RT027和RT078菌株已经获得了在二糖上生长的能力 皮毛糖比艰难梭菌的其他核糖型更有效。我们的初步数据表明机械 这两种结构型改善生长的碱基在遗传和机械上是不同的，这表明 在这些系统发育不同的核能中，改善了海藻糖代谢的收敛进化。此外， 我们发现，破坏RT027菌株利用海藻糖的能力极大地减弱了疾病 严重程度，表明海藻糖代谢有助于RT027和RT078的过度维质性质 菌株。 Trehalose是一种葡萄糖的二糖，在被授予后成为一种广泛使用的食物 FDA在2000年获得GRAS身份批准，EFSA在2001年在欧洲。 由于Alpha，Alpha 1-1连接，热与酸稳定，属性是糖添加剂的特性 比蔗糖甜45％。通常在蘑菇和贝类等食物中发现，海藻糖现在是 从碎牛肉到冰淇淋等各种食品和饮料产品。 在全球粮食供应中加入海藻糖与RT027和 RT078在2000年代初期的菌株，即使这些结构型也早在1985年就存在于1985年。 我们建议在RT027和 RT078菌株由于其能力更有效地代谢海藻糖并为医院做出了贡献 流行病。我们将在我们的实验室中使用两个最近开发的模型 艰难梭菌入侵的模型和艰难梭菌感染的人源化菌群模型，以研究 海藻糖和改善海藻糖代谢对RT027和RT078菌株引起C的能力的影响。 艰难的感染。我们还将研究改善RT027海藻糖代谢的机械基础 和RT078菌株。最后，我们将评估海藻糖代谢对殖民的影响的影响 这些高毒性艰难梭菌核糖型动物的动力学，疾病的严重程度和运输。下列 提出了具体目的：目标1。研究C.海藻糖代谢的机制。 艰难梭菌会增加疾病的严重程度。目标2。了解改善海藻糖的机械基础 RT027 C.艰难梭菌中的代谢。目标3。了解所获得的海藻糖操纵子的作用 RT078健身和动物运输。我们希望这项工作将在最近的添加之间建立联系 人类饮食中的海藻糖和艰难梭菌核糖型的出现。这将提供第一个 人类饮食改变的直接证据直接影响肠道感染的发病机理。