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: 8896409
• 负责人: Stephen Obaro
• 金额: $ 40.12万
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896409
• 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; Health; 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; diagnostic assay; disorder control; extracellular; global health; improved; innovation; insight; multidisciplinary; next generation; novel diagnostics; novel vaccines; pathogen; peripheral blood; protective efficacy; prototype; 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（由申请人提供）：伤寒是由沙门氏菌血清Typhi（S. typhi）引起的，它是一种人类特异性病原体。世界卫生组织（WHO）认为伤寒是全球健康问题，估计每年有2100万例，每年有200,000-600,000例死亡。在非洲和南亚，幼儿代表着一个疾病负担最高的亚组。疾病的发作是阴险的，临床诊断通常是不可靠的。通过血液或骨髓培养的明确诊断是劳动密集型，昂贵且侵入性的，灵敏度为40％至70％。谁建议常规的伤寒疫苗接种，但目前获得许可的疫苗仅提供55-75％的疾病保护。因此，迫切需要开发快速，敏感且廉价的诊断方法，以及伤寒发烧仍然是主要公共卫生负担的国家的更有效的疫苗。我们的长期目标是1）开发创新的分子诊断测定法，以快速和廉价地检测伤寒和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发展。我们的直接目标是获得疫苗感染的非洲儿童的全球基因表达和蛋白质组学特征，识别和验证 分类器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建立了一种菌血症监测系统。从一小群尼日利亚的伤寒儿童开始进行了一项试点研究。我们的初步数据显示，与其他菌血症感染相比，伤寒儿童的外周血中宿主反应的独特基因表达谱以及急性与康复期患者。在这里，我们假设可以获得基于周围血液和血清中宿主反应的不同分类剂基因和蛋白质，以区分伤寒和其他细菌感染和健康对照。我们的具体目的是：1）使用基因表达（GE）微阵列定义伤寒特异性宿主反应分类器基因，2）使用新建立的Typhi蛋白质组微阵列发现特定的血清抗型蛋白质蛋白，并使用急性Typhoid（Elisa）的急性Typhoid（ELISA）识别分类型和领域的field Indifestififier Genes andepe-和Field Indife-Test-test-test-test-test-test-test-test-test-test-test-test-test-test-test-test-test-test-test-test-test-test-tester基因相关。为了实现这些目标，我们组建了一个具有传染病，免疫学，分子基因组学/蛋白质组学，微阵列和生物信息学方面的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确定不同的分类器基因和蛋白质感染伤寒感染。将斑链球菌与其他菌血症区分开的分类器可以发展并提供快速，廉价，非侵入性和灵敏的分子诊断测定法。从我们新的定制全蛋白质伤寒微阵列获得的分类蛋白将提供针对下一代疫苗开发的靶向蛋白质和抗体的新见解。

项目成果

Molecular characterization of invasive Enterobacteriaceae from pediatric patients in Central and Northwestern Nigeria.

• DOI: 10.1371/journal.pone.0230037
• 发表时间: 2020
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Duru C;Olanipekun G;Odili V;Kocmich N;Rezac A;Ajose TO;Medugu N;Umoru D;Onuchukwu C;Munir H;Jibir BW;Farouk Z;Gambo S;Hassan-Hanga F;Olaosebikan R;Ebruke B;Esimone C;Obaro S
• 通讯作者: Obaro S

Pulmonary hypertension and right ventricular function in Nigerian children with sickle cell anaemia.

尼日利亚镰状细胞性贫血儿童的肺动脉高压和右心室功能。

• DOI: 10.1093/trstmh/trz038
• 发表时间: 2019
• 期刊: Transactions of the Royal Society of Tropical Medicine and Hygiene
• 影响因子: 2.2
• 作者: Peter,IgocheD;Asani,MustafaO;Abdullahi,ShehuU;Aliyu,Ibrahim;Obaro,StephenK;Bode-Thomas,Fidelia
• 通讯作者: Bode-Thomas,Fidelia

Phenotypic and molecular characterization of beta-lactam resistant Multidrug-resistant Enterobacterales isolated from patients attending six hospitals in Northern Nigeria.

• DOI: 10.1038/s41598-023-37621-z
• 发表时间: 2023-06-26
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Medugu, Nubwa;Tickler, Isabella A.;Duru, Carissa;Egah, Ruth;James, Abu Ocheiku;Odili, Vivian;Hanga, Fatima;Olateju, Eyinade Kudirat;Jibir, Binta;Ebruke, Bernard E.;Olanipekun, Grace;Tenover, Fred C.;Obaro, Stephen K.
• 通讯作者: Obaro, Stephen K.