Integrated discovery and development of innovative TB Diagnostics

产品说明： 尽管存在治愈性疗法，但结核病仍然是全世界细菌病原体导致死亡的主要原因。有效的结核病控制需要对传染性病例进行早期诊断和治疗，以防止疾病的进一步传播。大部分问题源于传统结核病诊断的失败，传统结核病诊断依赖于痰涂片显微镜检查，在较小程度上依赖于疾病和耐药性表型的培养确认。不仅痰涂片的诊断率低，而且结核杆菌培养物的生长速度也非常缓慢。由于耐药性传统上是通过培养来评估的，因此耐药结核病通常在开始经验性药物治疗方案后数月才被发现。这些延误不仅导致接受不适当治疗方案的患者获得进一步的耐药性，而且还导致耐药微生物的感染延长，从而导致耐药菌株的传播。最近发展的快速分子诊断有望彻底改变结核病控制。此类检测可直接在痰液或其他临床样本上进行，并依赖于MTB遗传特征以及耐药相关突变的快速检测。临床研究表明，它们比痰涂片镜检更好，并可靠地识别对一线药物利福平的耐药性。然而，这些工具受到两个重要限制。首先，目前的平台比培养敏感性低得多，并且经常错过涂片阴性结核病。其次，我们对表型耐药的遗传决定因素的认识存在差距，这限制了可以检测到耐药的药物范围。在这里，我们建议通过多学科合作来解决这些差距，重点是发现新的耐药生物标志物，确定针对MTB DNA检测的最佳临床采样策略，以及开发基于灵敏微阵列的快速诊断。我们的长期目标是制定一项诊断战略，改善儿童和DR结核病的诊断，并阻止疾病的进一步传播。

DESCRIPTION: 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.