Global Genomic and Proteomic Profiling of African Children With Typhoid Fever
Condition: Typhoid Fever
MeSH terms: Typhoid Fever; Fever
Study type: Observational

Summary: 
      To develop a rapid, sensitive, and inexpensive diagnostic method, as well as more efficacious
      vaccine, for countries where typhoid fever remains a major public health burden.
    

Detailed description: 
      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. The 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.

      The 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. A bacteremia surveillance system was
      established in central Nigeria in 2008; a pilot study was initiated from a small cohort from
      this system composed of children with typhoid fever.

      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, it is hypothesized 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.

      Specific aims:

        1. Define typhoid fever-specific host response classifier genes using gene expression (GE)
           micro-arrays,

        2. Discover specific serum anti-typhoid fever proteins using newly established S. Typhi
           proteome micro-arrays 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, a multidisciplinary team with expertise in infectious
      disease, immunology, molecular genomics/proteomics, micro-arrays, and bioinformatics has been
      assembled to ensure success of this project. These studies will identify distinct classifier
      genes and proteins of 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 the new, custom whole-proteome typhoid fever
      micro-arrays will provide new insights of targeted proteins and antibodies for
      next-generation vaccine development.
    

Observational model: Ecologic or Community
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Children 1-14 years old who present with an acute febrile illness that is clinically
        suggestive of bacteremia.
      
Biospecimen description: 
      Blood, urine, stool, nasopharyngeal swab/aspirate as well as cerebrospinal fluid (CSF),
      pleural fluid, induced sputum, gastric aspirates or synovial fluid with clinical indication.