Improving diagnostic capabilities for typhoid fever

项目总结/摘要 目前，在美国的伤寒流行地区，还没有很好的伤寒（或携带）诊断测试方法。 世界这种缺陷使适当的抗微生物剂的靶向给药复杂化，并且是一种潜在的抗微生物剂。 这是更广泛地支持伤寒控制和疫苗计划的主要障碍。在 这两个阶段R21（勘探）/ R33（扩展和开发）的建议，我们建立在一个 正在进行的国际合作努力，以支持以下具体目标和里程碑： R21：第1年和第2年：创新假设驱动项目 1.抗S抗体的评价。伤寒伊加ALS液体检测系统作为伤寒诊断。 2.尿液ELISA或试纸条测定的开发。 3.筛选无症状携带者血清中针对S.伤寒抗原表达 体内和独特的载体状态。 在第2年（R21）结束前，我们建议（1）至少开发出一个原型 在孟加拉国达卡进行的后续评价中使用的方法（基于ALS或基于尿液）， 和（2）筛选携带者血液以评估是否存在独特信号。 R33：第3-5年：额外的创新探索性研究和扩大诊断开发 4.孟加拉国达卡的现场（流行区）试验原型测定（ALS和/或尿液 如果有希望，从R21阶段开始。 5.先进的携带者诊断，如果有希望的话。 如果没有希望： 6.进一步探索使用微流控甘露糖结合凝集素“捕获”系统， 提高S.伤寒在急性感染病人的血液中。 7.探讨基于γ干扰素的伤寒检测方法。 8.探索诊断检测S.伤寒mRNA/cDNA（与gDNA相反）在 伤寒患者的血液，以提高敏感性。 到第5年年底（R33）的主要交付成果：制定诊断方法， 灵敏度和特异性优于流行区的现有检测方法（我们的初始目标是灵敏度>90%; 特异性>90%;与流行区目前可用/使用的测定相比有显著改进）。

PROJECT SUMMARY/ABSTRACT Currently, there is no good diagnostic test for typhoid fever (or carriage) in typhoid endemic areas of the world. This deficiency complicates the targeted administration of appropriate antimicrobials, and is a major impediment to the more widespread endorsement of typhoid control and vaccine programs. In this two stage R21 (exploration)/ R33 (expansion and development) proposal, we build upon an ongoing international collaborative effort to support the following specific aims and milestones: R21: years 1 and 2: innovative hypothesis-driven projects 1. Evalation of anti-S. Typhi IgA ALS fluid detection system as a typhoid diagnostic. 2. Development of urine ELISA or dipstick assay. 3. Screen asymptomatic carrier serum for antibodies targeting S. Typhi antigens expressed in vivo and unique to the carrier state. Main milestones by the end of year 2 (R21), we propose (1) to have developed at least one prototype approach (either ALS-based or urine-based) to use in subsequent evaluations in Dhaka, Bangladesh, and (2) to have screened carrier blood to assess if a unique signal is present. R33: years 3-5: additional innovative exploratory research and expanded development of diagnostics 4. Field (endemic zone) test prototype assays in Dhaka, Bangladesh (ALS and/or urine device[s]) from R21 phase, if promising. 5. Advance carrier diagnostic, if promising. If not promising: 6. Further explore the use of a microfluidic mannose binding lectin "capture" system to increase recovery of S. Typhi in the blood of acutely infected patients. 7. Explore interferon-gamma based detection assay (IGA) approach for typhoid. 8. Explore the ability to diagnostically detect S. Typhi mRNA/cDNA (as opposed to gDNA) in the blood of infected humans with typhoid, to improve sensitivity. Main deliverable by the end of year 5 (R33): development of diagnostic approach(es) that is/are more sensitive and specific than current assays in an endemic zone (our initial goal will be >90% sensitivity; >90% specificity; a significant improvement over assays currently available/in use in endemic zones).