Identification of Salmonella Genes Important for Systemic Colonization

鉴定对系统定植重要的沙门氏菌基因

基本信息

批准号：
8134996
负责人：
HELENE L ANDREWS-POLYMENIS
金额：
$ 39.86万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-25 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8134996
关键词：
Acquired Immunodeficiency Syndrome Acute Africa South of the Sahara Age Animal Model Animals Area Bacteremia Bacteria Bacterial Proteins Biological Assay Biological Models Candidate Disease Gene Cause of Death Cells Cessation of life Child Cistrons Collection Complement Development Disadvantaged Disease Frequencies Gene Deletion Gene Proteins Genes Genetic Genetic Screening Genome Gentamicins Goals HIV Health Hour Immune system Immunocompromised Host In Vitro Individual Infection Invaded Lead Libraries Methods Modeling Molecular Molecular Genetics Mus Oligonucleotide Microarrays Organ Organism Parasites Persons Phenotype Process Public Health Relative (related person)Resistance Resources Salmonella Salmonella enterica Salmonella infections Salmonella typhimurium Screening procedure Serotyping Site Spleen Systemic disease Systemic infection Therapeutic Agents Transcript Vaccines Virulence Virus Work antimicrobial base combat deletion library fitness foodborne foodborne illness gene function genetic manipulation genome sequencing high throughput screening in vivo intraperitoneal macrophage mortality mutant new technology novel pathogen promoter recombinase tool tool development

项目摘要

DESCRIPTION (provided by applicant): We will use the power of complete genome sequences and forward genetics to identify novel genes that allow a bacterial pathogen to colonize systemic organs in murine models. Non-typhoidal Salmonella (NTS) are food-borne bacterial pathogens that cause hundreds of millions of cases of diarrheal disease and hundreds of thousands of deaths due to bacteremia annually worldwide. Salmonella enterica serotype Typhimurium is an appropriate model to determine the requirements for systemic infection by NTS as this serotype causes more cases of NTS bacteremia, in children under the age of 5 and in HIV infected individuals, than any other serotype. The availability of complete genome sequence information, the ease of genetic manipulation, and the availability of numerous animal models make serot. Typhimurium an excellent model system. We have generated a collection of 1030 targeted deletion strains in serot. Typhimurium (approximately 25% of the genome), developed a novel oligonucleotide microarray to assay this collection of mutants, and begun forward genetic screening of this mutant collection both in vitro and in vivo in murine models of systemic colonization. We wish to complete the development of these tools and progress to more comprehensive studies of a subset of genes involved in systemic colonization a process that occurs during NTS bacteremia caused by this organism. We will approach this goal by: 1. Completion of our deletion library in all non-essential genes in Salmonella Typhimurium, 2. Screening our complete deletion collection in murine models to identify new genes involved in systemic colonization, 3. Confirming each mutant as defective for systemic colonization, 4. Characterizing mutants that are defective for systemic colonization for their ability to associate with, invade, and replicate in cultured macrophages. PUBLIC HEALTH RELEVANCE: Salmonella is a leading cause of food borne illness, causing ~1.4 million cases of diarrheal disease per year and is the single most common cause of death from food-borne illnesses associated with viruses, parasites or bacteria in the US primarily in immunocompromised persons. In young children and HIV-infected individuals, non-typhoidal Salmonellae (NTS) frequently cause systemic infection that is associated with high mortality. The rise of AIDS in many parts of the world, notably in sub- Saharan Africa, has resulted in a dramatic increase in the frequency of NTS-associated systemic infections. The work described in this project will provide novel targets for vaccines and treatments for acute systemic disease that results from Salmonella infection. This work will have a direct impact on public health.

描述（由申请人提供）：我们将利用完整的基因组序列和正向遗传学的力量来识别允许细菌病原体在鼠模型中定居全身器官的新型基因。非细类沙门氏菌（NTS）是食源性细菌病原体，导致数亿例腹泻病病例，每年由于全球细菌而导致数以千计的死亡。沙门氏菌肠形型鼠伤寒是确定NTS全身感染要求的合适模型，因为该血清型会导致5岁以下的5岁儿童和HIV感染的个体，而不是其他任何血清型。完整的基因组序列信息的可用性，遗传操作的易于性以及众多动物模型的可用性使得血清作品。鼠伤寒是一种出色的模型系统。我们已经在血清索产品中生成了1030个目标删除菌株的集合。鼠伤寒（约占基因组的25％），开发了一种新型的寡核苷酸微阵列来测定这种突变体的集合，并开始在全身定植的鼠模型中对这种突变体收集的遗传筛查。我们希望完成这些工具的开发，并进步，以对全身定植的一部分基因进行更全面的研究，该过程在这种生物体引起的NTS菌血症期间发生的过程。我们将通过以下方式实现这一目标：1。在鼠伤寒沙门氏菌的所有非必需基因中完成我们的缺失库，2。筛选我们在鼠模型中的完整删除集合，以确定与全身性殖民化的全身性殖民化的新基因，以确保每个突变体的有缺陷，以表征全身性突变，以使其具有不足的统治，以表征他们的系统性，以使其具有不良的统治，以使其与系统性的统治相关，以使其具有系统性的统治，以使其与系统性统治相关。巨噬细胞。公共卫生相关性：沙门氏菌是造成食物出生疾病的主要原因，每年造成约140万例腹泻病，是美国主要在免疫副不动的人群中主要是与病毒，寄生虫或细菌相关的食物，寄生虫或细菌相关的最常见的死亡原因。在幼儿和感染HIV的个体中，非细类沙门氏菌（NTS）经常引起与高死亡率有关的全身感染。艾滋病在世界许多地方，尤其是在撒哈拉以南非洲的兴起，导致了与NTS相关的全身感染的频率急剧增加。该项目中描述的工作将为沙门氏菌感染引起的急性全身性疾病的疫苗和治疗方法提供新的靶标。这项工作将对公共卫生产生直接影响。