Integrated discovery and development of innovative TB Diagnostics

尽管有治疗方法可用，结核病仍然是死于非传染性疾病的首要原因。 世界各地的细菌病原体。有效的结核病控制需要早期诊断和治疗感染性疾病 防止疾病进一步传播的病例。这个问题很大程度上源于 传统的结核病诊断依赖于痰涂片显微镜，在较小程度上依赖于培养确认 疾病和耐药表型。不仅是低诊断率的痰涂片，培养 众所周知，结核分枝杆菌生长缓慢。由于耐药性的传统评估方法是 在培养中，耐药结核病通常在经验药物方案开始几个月后被发现。这些 延误不仅会导致接受不充分方案的患者获得进一步的耐药性，而且 也与那些携带抗药性生物体的人的长期传染性和随之而来的药物传播有关 耐药菌株。 快速分子诊断技术的最新发展有望给结核病控制带来革命性的变化。这样的测试可以 直接对痰或其他临床样本进行检测，并依赖于对结核杆菌基因的快速检测 签名以及与抗药性相关的突变。临床研究表明，它们的表现更好。 比痰涂片镜检更能可靠地确定对一线药物利福平的耐药性。然而， 这些工具有两个重要的局限性。首先，当前平台的敏感度远低于 培养并经常漏诊涂片阴性结核病。第二，我们对基因的了解存在差距 表型耐药性的决定因素限制了可检测到耐药性的药物谱。这里, 我们建议通过多学科合作来解决这些差距，强调发现新的 耐药的生物标记物、最佳临床抽样策略的确定 结核分枝杆菌DNA与开发一种敏感的基于微阵列的快速诊断。我们的长期目标是 制定诊断战略，改进对儿童和DR结核病的诊断，并阻止进一步 疾病的传播。

Despite the availability of curative therapy, tuberculosis continues to be the leading cause of death from a bacterial pathogen worldwide. Effective TB control requires the early diagnosis and treatment of infectious cases to prevent further transmission of the disease. Much of the problem stems from the failure of traditional TB diagnostics which rely on sputum smear microscopy and to a lesser extent culture confirmation of disease and drug resistance phenotypes. Not only are sputum smears of low diagnostic yield, cultures for Mycobacterium tuberculosis grow notoriously slowly. Since drug resistance is traditionally assessed by culture, drug resistant TB is often detected months after the initiation of empirical drug regimens. These delays not only lead to the acquisition of further resistance in patients receiving inadequate regimens but also to the prolonged infectiousness of those with resistant organisms and the consequent spread of drug resistant strains. The recent development of rapid molecular diagnostics promises to revolutionize TB control. Such tests can be performed directly on sputum or other clinical samples and rely on the rapid detection of MTB genetic signatures as well as resistance-associated mutations. Clinical studies demonstrate that they perform better than sputum smear microscopy and reliably identify resistance to the first line drug, rifampicin. However, these tools suffer from two important limitations. First, current platforms are substantially less sensitive than culture and often miss smear negative TB. And secondly, gaps in our knowledge of the genetic determinants of phenotypic resistance limit the spectrum of drugs to which resistance can be detected. Here, we propose to address these gaps through a multi-disciplinary collaboration emphasizing discovery of new biomarkers of resistance, the identification of optimal clinical sampling strategies directed toward detection of MTB DNA and the development of a sensitive micro-array based rapid diagnostic. Our long-term goal is to develop a diagnostic strategy that will improve the diagnosis of childhood and DR TB and stem the further spread of the disease.