Propagation and Characterization of Phage Related to Human Growth

与人类生长相关的噬菌体的繁殖和表征

• 批准号: 10668108
• 负责人: Lori R Holtz
• 金额: $ 23.48万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-20 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10668108
• 关键词: Affect; Agar; Age; Animal Model; Bacteria; Bacterial Genome; Bacteriolysis; Bacteriophages; Biology; Cause of Death; Cell Separation; Cells; Child; Child Development; Child Health; Childhood; Colorectal Cancer; Communities; Complex; DNA amplification; Data; Diabetes Mellitus; Diagnosis; Disease; Disease Marker; Dyes; Enteral; Equilibrium; Feces; Fluorescence-Activated Cell Sorting; Functional disorder; Future; Genome; Genomics; Growth; Health; Human; Human body; Hypertension; Immune response; Impairment; Individual; Inflammatory; Inflammatory Bowel Diseases; Intervention; Knowledge; Label; Link; Longitudinal cohort; Lytic; Mechanics; Methods; Molds; Necrotizing Enterocolitis; Nucleic Acids; Population; Preschool Child; Prevention; Process; Prokaryotic Cells; Publishing; Reagent; Rural; Sampling; Structure; Techniques; Viral; Virus; bacterial community; bacteriome; deep sequencing; dysbiosis; experimental study; fitness; genetic signature; global health; gut health; gut microbiome; in silico; interest; low and middle-income countries; microbial; microbial signature; mortality; novel; novel strategies; optical spectra; prevent; screening; stool sample; virome; virus culture

Project Description Bacteriophage (phage) are viruses that infect prokaryotes. Bacteriophage can destroy the bacterial cell they infect (bacteriolysis), and thereby mold bacterial populations. Our incomplete knowledge of phage biology, in particular phage-bacterial pairing, the range of bacterial hosts for a given phage, and the effect of an introduced phage on phage-bacteria community dynamics limits our ability to understand how phage impact gut health. The human gut contains a highly complex community of bacteria and phage. Alterations in bacteriophage communities are associated with disorders such as inflammatory bowel disease, diabetes, hypertension, and colorectal cancer. Stunting (poor linear growth) adversely affects one-third of the half-billion preschool children in low and middle-income countries and is associated with ~20% of all-cause deaths before age five. Stunting is believed to be a consequence of environmental enteric dysfunction (EED). We recently defined the comprehensive gut virome and the bacterial gut microbiome in a longitudinal cohort of rural Malawian children with EED. We found 13 bacteriophage that were differentially associated with linear growth. Twelve of the 13 bacteriophage were associated with subsequent poor growth velocity. Intriguingly, we found an inverse relationship between bacteria and bacteriophage richness in children with subsequent poor linear growth (bacteriophage richness diminishes as bacterial richness increases in children with poor growth). Our data suggest that disruption of the equilibrium between bacteria and bacteriophage communities might impair childhood linear growth. This observation that changes in the phage community are associated with subsequent linear growth is intriguing as there is currently no way to treat or prevent EED and stunting. Additionally, the pathophysiology underlying EED is not well understood, and there currently is not a reliable marker of disease. Therefore, further understanding of these bacteriophage as either drivers or markers of disease would be a significant advance for the field. We suggest that further characterization, and potentially future manipulation, of these microbial signatures may reveal novel avenues for prevention, diagnosis, or treatment of EED and stunting. Here we aim to advance understanding of phage biology, global gut health, and child health and development. We will identify and grow bacterial host(s) of the phages of interest, culture phages, and further characterize them. While we propose to apply our methods to study phage in the context of EED, execution of this approach will also provide a much-needed roadmap for future studies of phage in other disorders.

项目描述 噬菌体是感染原核生物的病毒。噬菌体可以破坏细菌细胞 它们感染（溶菌作用），从而使细菌群体成型。我们对噬菌体的不完全了解 生物学，特别是噬菌体-细菌配对，给定噬菌体的细菌宿主范围，以及噬菌体的作用， 引入的噬菌体对噬菌体-细菌群落动力学的影响限制了我们理解噬菌体如何影响 肠道健康人类肠道含有高度复杂的细菌和噬菌体群落。的改变 噬菌体群落与诸如炎症性肠病，糖尿病， 高血压和结肠直肠癌。 发育迟缓（线性生长不良）对5亿学龄前儿童中的三分之一产生了不利影响， 在中等收入国家，与五岁之前的所有原因死亡的约20%有关。据信， 是环境肠道功能障碍（EED）的结果。我们最近定义了综合肠道 马拉维农村EED儿童纵向队列中的病毒组和细菌肠道微生物组。 我们发现了13个与线性生长有差异的噬菌体。13人中的12人 噬菌体与随后的不良生长速度有关。有趣的是，我们发现了一个相反的 随后线性生长不良的儿童中细菌和噬菌体丰度之间的关系 （在生长不良的儿童中，噬菌体丰富度随着细菌丰富度的增加而减少）。我们的数据 这表明细菌和噬菌体群落之间平衡的破坏可能会损害 童年线性成长 噬菌体群落的变化与随后的线性生长相关的这一观察结果是， 有趣的是，目前还没有办法治疗或预防EED和发育迟缓。此外，病理生理学 潜在的EED还没有被很好地理解，目前还没有可靠的疾病标志物。因此，我们建议， 进一步了解这些噬菌体作为疾病的驱动因素或标志物将是一个重要的 前进到外地。我们建议，进一步的表征，并可能在未来的操纵，这些 微生物特征可能揭示预防、诊断或治疗EED和发育迟缓的新途径。 在这里，我们的目标是促进对噬菌体生物学，全球肠道健康以及儿童健康和发育的理解。 我们将鉴定和培养感兴趣的细菌的细菌宿主，培养细菌，并进一步表征 他们虽然我们建议将我们的方法应用于在EED的背景下研究噬菌体，但本发明的实施并不局限于此。 这种方法也将为今后在其他疾病中研究噬菌体提供急需的路线图。