Modulation of EPEC susceptibility and severity by the microbiome

微生物组对 EPEC 易感性和严重程度的调节

• 批准号: 9481667
• 负责人: R William DePaolo
• 金额: $ 19.39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9481667
• 关键词: Accounting; Address; Africa South of the Sahara; Age; Animal Model; Antibiotics; Architecture; Bacteria; Biological; Cause of Death; Cessation of life; Child; Chronic; Clinical; Cotrimoxazole; Cyclophosphamide; Data; Diarrhea; Disease; Enteral; Environment; Feces; Gene Expression; Genetic; Genomics; Germ-Free; Goals; HIV; HIV Infections; HIV-1; Human; Immune; Immunology; Immunosuppression; Infant; Infection; Intestines; Knowledge; Literature; Metabolic; Microbiology; Mus; Mutation; Outcome; Pathogenicity; Population; Predisposition; Ribosomal RNA; Severities; Testing; Viremia; Virulence; Virulence Factors; Virus Diseases; base; co-infection; differential expression; effective therapy; enteric pathogen; enteropathogenic Escherichia coli; fecal transplantation; gut microbiome; innovation; interdisciplinary approach; killings; microbial; microbiome; microbiota; mortality; prophylactic; reconstitution; restoration; transcriptome sequencing; transcriptomics; treatment strategy

Project Summary (Abstract) Globally, there are nearly 1.7 billion cases of enteric GI infections that cause diarrheal disease every year. More disturbing, is that diarrheal disease caused by enteric pathogens kills over 2,000 children every day and is the second leading cause of death among children under the age of five. Enteropathogenic Escherichia coli (EPEC) is a common culprit of diarrheal disease in Sub-Saharan Africa, accounting for roughly 10% of all diarrheal deaths. EPEC infections are disproportionately high in children with HIV and cause more frequent and prolonged diarrhea episodes than in the uninfected counterparts. Despite the immune deficiency caused by HIV infection, EPEC is the only enteric pathogen that is frequently and consistently prevalent in this population, suggesting that more than just immune suppression may be involved in this relationship. Further, we have found that HIV uninfected children receiving the antibiotic cotrimoxazole (CTX) also have higher susceptibility and severity of EPEC infection. This is especially intriguing as both antibiotic use and HIV-infection have been correlated with a reduction in gut microbial diversity and has prompted us to hypothesize that the susceptibility and clinical severity of EPEC infection observed in HIV-infected and antibiotic-treated children is a consequence of a microbiome reduced in diversity, which promotes changes in the metabolic and virulence gene expression by EPEC. We will test this in two aims. In Aim 1 we will assess the microbiome as a potential modulator of EPEC virulence by performing 16S sequencing on HIV+ and antibiotic-treated children to confirm reduced diversity and to compare bacterial compositions, we will examine the association between EPEC strain and clinical outcomes and we will use germ-free mice reconstituted with human stool to evaluate whether changes in diversity impact EPEC infection. In Aim 2, we will determine genetic alterations in the clinical isolates using microbial transcriptomics and then we will determine whether the genetic data is correct by assessing virulence in an animal model and we will determine whether restoring microbial diversity via a fecal microbiota transplant would be an effective treatment option.

项目摘要（摘要） 在全球范围内，每年有近17亿例肠道GI感染病例导致腹泻病。更 令人不安的是，由肠道病原体引起的腹泻病每天造成2,000多名儿童死亡， 是五岁以下儿童死亡的第二大原因。肠致病性大肠杆菌（EPEC） 是撒哈拉以南非洲地区疟疾疾病的罪魁祸首，约占所有疟疾的10 死亡EPEC感染在感染艾滋病毒的儿童中不成比例地高， 腹泻发作比未感染的同行。尽管艾滋病毒感染导致免疫缺陷， EPEC是唯一的肠道病原体，是经常和一贯流行的这一群体，这表明 这种关系可能不仅仅涉及免疫抑制。此外，我们发现艾滋病毒 接受抗生素复方新诺明（CTX）治疗的未感染儿童也有较高的易感性和严重性， EPEC感染。这是特别有趣的，因为抗生素的使用和艾滋病毒感染都与艾滋病有关。 肠道微生物多样性的减少，促使我们假设易感性和临床严重性 在艾滋病毒感染和疟疾治疗的儿童中观察到的EPEC感染是微生物组的结果 减少的多样性，这促进了EPEC的代谢和毒力基因表达的变化。我们将 测试这两个目标。在目标1中，我们将通过以下方法评估微生物组作为EPEC毒力的潜在调节剂： 对HIV阳性和接受过抗逆转录病毒治疗的儿童进行16 S测序，以确认减少的多样性， 细菌组成，我们将检查EPEC菌株和临床结果之间的关联，我们将 使用人类粪便重建的无菌小鼠来评估多样性的变化是否影响EPEC 感染在目标2中，我们将使用微生物转录组学确定临床分离株的遗传变异 然后我们将通过评估动物模型的毒力来确定遗传数据是否正确， 我们将确定通过粪便微生物群移植恢复微生物多样性是否是一种有效的方法， 治疗选择