Global Genomic and Proteomic Profiling of African Children with Typhoid Fever

描述（由申请人提供）：伤寒是由伤寒沙门氏菌引起的，伤寒沙门氏菌是一种人类特有的病原体。世界卫生组织（世卫组织）承认伤寒是一个全球性的健康问题，估计每年有2 100万例病例和20万至60万人死亡。在非洲和南亚，幼儿是疾病负担最重的一个亚群体。该病的发病是隐匿的，临床诊断往往不可靠。通过血液或骨髓培养进行明确诊断是劳动密集型的，昂贵的，侵入性的，敏感性为40%至70%。世卫组织建议常规接种伤寒疫苗，但目前许可的疫苗只能提供55-75%的预防该疾病的保护。因此，迫切需要开发快速、敏感和廉价的诊断方法，以及为伤寒仍然是主要公共卫生负担的国家开发更有效的疫苗。我们的长期目标是：1)开发创新的分子诊断方法，以快速和廉价地检测伤寒；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。我们的直接目标是获得感染斑疹伤寒沙门氏菌的非洲儿童的全球基因表达和蛋白质组学谱，鉴定和验证

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.