Global Genomic and Proteomic Profiling of African Children with Typhoid Fever

非洲伤寒儿童的全球基因组和蛋白质组分析

• 批准号: 8531850
• 负责人: Stephen Obaro
• 金额: $ 38.12万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-17 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531850
• 关键词: ATP-Binding Cassette Transporters; Acute; African; Algorithms; Antibodies; Area; Asia; Bacteremia; Bacteria; Bacterial Infections; Bioinformatics; Biological Assay; Biological Markers; Blood; Bone Marrow; Cessation of life; Child; Complex; Country; Custom; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disease; Disease Outbreaks; Ensure; Enteral; Enzyme-Linked Immunosorbent Assay; Fever; Gene Chips; Gene Cluster; Gene Expression; Gene Expression Profile; Gene Proteins; Genes; Genomics; Goals; Housing; Human; Immune response; Infection; Infectious Disease Immunology; Inflammatory; Knowledge; Lead; Licensing; Molecular; Molecular Profiling; Nigeria; Onset of illness; Pathway interactions; Patients; Peptides; Persons; Phase; Pilot Projects; Primary Prevention; Procedures; Process; Proteins; Proteome; Proteomics; Public Health; Publishing; Recovery; Recruitment Activity; Resources; Salmonella; Salmonella typhi; Sampling; Serological; Serum; South Africa; Subgroup; System; Testing; Time; Typhoid Fever; Vaccination; Vaccine Therapy; Vaccines; Validation; World Health Organization; aged; base; burden of illness; clinical Diagnosis; cohort; disorder control; extracellular; global health; improved; innovation; insight; multidisciplinary; next generation; novel diagnostics; novel vaccines; pathogen; peripheral blood; protective efficacy; prototype; public health relevance; response; success; tool; vaccine development

DESCRIPTION (provided by applicant): Typhoid fever is caused by Salmonella enteric serovar Typhi (S. typhi), a human specific pathogen. The World Health Organization (WHO) recognizes typhoid fever as a global health problem, with an estimated 21 million cases and 200,000-600,000 deaths annually. In Africa and South Asia, young children represent a subgroup with the highest disease burden. The onset of the illness is insidious and clinical diagnosis is often unreliable. Definitive diagnosis through blood or bone-marrow culture is labor-intensive, expensive, and invasive, with a sensitivity of 40 to 70%. WHO recommends routine typhoid fever vaccination but currently licensed vaccines provide only 55-75% protection against the disease. Therefore, there is an urgent need to develop rapid, sensitive, and inexpensive diagnostic methods, as well as more efficacious vaccines for countries where typhoid fever remains a major public health burden. Our long term goals are 1) to develop innovative molecular diagnostic assays for rapid and inexpensive detection of typhoid fever and, 2) to better understand the molecular mechanisms of host response to facilitate the development of next-generation typhoid fever vaccines. Our immediate objective is to obtain global gene expression and proteomic profiles of S. typhi- infected African children, identify and validate the classifier genes and proteins as potential diagnostic biomarkers and vaccine targets. We have already established a bacteremia surveillance system in central Nigeria since 2008. A pilot study was initiated from a small cohort of Nigerian children with typhoid fever. Our preliminary data showed unique gene expression profiles of host response in peripheral blood of children with typhoid fever compared with other bacteremic infections, as well as patients in acute vs. convalescent phase. Here, we hypothesize that distinct classifier genes and proteins based on host response in the peripheral blood and serum can be obtained to discriminate typhoid fever from other bacteremic infections and healthy controls. Our specific aims are: 1) Define typhoid fever-specific host response classifier genes using gene expression (GE) microarrays, 2) Discover specific serum anti-typhoid fever proteins using newly established S. typhi proteome microarrays and develop prototype serologic assay for acute typhoid (ELISA) 3) Validate classifier genes and field-test prototype ELISAs using new, independent cohorts. To accomplish these objectives, we have assembled a multidisciplinary team with expertise in infectious disease, immunology, molecular genomics/proteomics, microarrays, and bioinformatics to ensure success of this project. These studies will identify distinct classifier genes and proteins f typhoid fever infection based on immunological responses. Classifiers that discriminate S. typhi from other bacteremia are possible to develop and offer rapid, inexpensive, non-invasive, and sensitive molecular diagnostic assays specific for typhoid fever. Classifier proteins obtained from our new, custom whole-proteome typhoid fever microarrays will provide new insights of targeted proteins and antibodies for next-generation vaccine development.

描述（申请人提供）：伤寒是由人类特有的病原体伤寒沙门氏菌（S.typhi）引起的。世界卫生组织 (WHO) 认为伤寒是一个全球性的健康问题，估计每年有 2100 万病例和 200,000-600,000 人死亡。在非洲和南亚，幼儿是疾病负担最高的亚群。该病起病隐匿，临床诊断往往不可靠。通过血液或骨髓培养进行确诊是一项劳动密集型、昂贵且具有侵入性的工作，敏感性为 40% 至 70%。世卫组织建议常规接种伤寒疫苗，但目前获得许可的疫苗只能提供 55-75% 的预防这种疾病的能力。因此，迫切需要为伤寒仍然是主要公共卫生负担的国家开发快速、灵敏且廉价的诊断方法以及更有效的疫苗。我们的长期目标是 1) 开发创新的分子诊断方法，以快速、廉价地检测伤寒，2) 更好地了解宿主反应的分子机制，以促进下一代伤寒疫苗的开发。我们的近期目标是获得感染伤寒沙门氏菌的非洲儿童的全球基因表达和蛋白质组图谱，识别并验证 分类基因和蛋白质作为潜在的诊断生物标志物和疫苗靶标。自 2008 年以来，我们已经在尼日利亚中部建立了菌血症监测系统。一项试点研究是从一小群患有伤寒的尼日利亚儿童中发起的。我们的初步数据显示，与其他菌血症感染以及急性期与恢复期患者相比，伤寒儿童外周血中宿主反应的独特基因表达谱。在这里，我们假设可以获得基于外周血和血清中宿主反应的不同分类基因和蛋白质，以区分伤寒与其他菌血症感染和健康对照。我们的具体目标是：1) 使用基因表达 (GE) 微阵列定义伤寒特异性宿主反应分类基因，2) 使用新建立的伤寒沙门氏菌蛋白质组微阵列发现特定的血清抗伤寒蛋白，并开发急性伤寒的原型血清学检测方法(ELISA) 3) 使用新的独立队列验证分类基因和现场测试原型 ELISA。为了实现这些目标，我们组建了一支拥有传染病、免疫学、分子基因组学/蛋白质组学、微阵列和生物信息学专业知识的多学科团队，以确保该项目的成功。这些研究将根据免疫反应识别伤寒感染的不同分类基因和蛋白质。可以开发区分伤寒沙门氏菌和其他菌血症的分类器，并提供针对伤寒的快速、廉价、非侵入性和灵敏的分子诊断测定。从我们的新型定制全蛋白质组伤寒微阵列中获得的分类蛋白将为下一代疫苗开发提供有关目标蛋白和抗体的新见解。