Exploring the Early Tuberculosis Spectrum Through Highly-Sensitive Mtb DNA Detection

通过高灵敏度 Mtb DNA 检测探索早期结核病谱

• 批准号: 10419579
• 负责人: Yingda Linda Xie
• 金额: $ 2.77万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10419579
• 关键词: Adult; Africa; Biological Markers; Biology; Blood; Clinical; Clinical Microbiology; Communicable Diseases; Containment; DNA; Data; Demographic Factors; Detection; Disease; Funding; Gene Expression Profile; Genetic Transcription; Growth; Individual; Messenger RNA; Microbiology; Morbidity - disease rate; Mycobacterium tuberculosis; Natural History; Parents; Role; Signs and Symptoms; Sputum; Testing; Tuberculosis; curative treatments; detection assay; detection test; diagnostic accuracy; follow-up; mortality; predictive signature; programs; risk stratification; scale up; transmission process

ABSTRACT Tuberculosis (TB, Mtb) remains one of the leading infectious disease killer globally, despite the availability of curative treatment for most individuals. The ability to identify TB which has progressed beyond bacterial containment associated with latency but not yet reached the burden of culture-positive, symptomatic active disease could have far- reaching impact in thwarting transmission and decreasing individual morbidity and mortality. The global scale-up of ultra-sensitive Mtb DNA detection assays, such as the WHO-recommended GeneXpert MTB/RIF Ultra (Ultra), presents a critical opportunity to identify this incipient, pre-cultivatable disease stage. We hypothesize that sputum Mtb DNA-positive/culture-negative individuals are more likely to have incipient TB than Mtb DNA-negative/culture-negative (TB-negative) individuals. To test this hypothesis, we initiated a substudy to an R01-funded Ultra diagnostic accuracy study of adults in Africa with signs/symptoms of TB to evaluate the biology and natural history Ultra Mtb DNA- positive/culture-negative individuals. In Aim 1, we will characterize host clinical and demographic factors associated with sputum Mtb DNA-positive/culture-negative status and characterize these individuals on the spectrum of Mtb infection using pre-validated blood transcriptional signatures predictive of progression to active TB. In Aim 2, we will evaluate and compare microbiologic indicators of TB disease between Mtb DNA positive/culture negative and TB-negative individuals. Specifically, we propose to investigate the presence of Mtb mRNA from sputum and evaluate for differentially culturable Mtb from extended incubation and culture supplemented with growth promoting factors. Finally, we will evaluate the natural history of Mtb DNA- positive/culture-negative individuals with respect to TB-negative controls using longitudinal clinical, microbiologic, and host transcriptional data collected over a 12- month follow-up period in the parent study. Together, these proposed studies will inform the utility of ultrasensitive Mtb DNA detection tests for early TB risk stratification and characterize the natural history and biomarkers of culture-negative TB.

抽象的 结核病（TB，MTB）仍然是全球领先的传染病杀手之一， 尽管大多数人都可以治疗治疗方法。识别能力 结核病已经超出了与潜伏期相关的细菌遏制的发展 然而，达到了培养阳性，有症状的活动疾病的负担 在挫败传播和降低个人发病率和降低的影响方面产生影响 死亡。超敏感的MTB DNA检测测定法的全球规模扩大，例如 谁推荐的GenExpert MTB/RIF Ultra（Ultra）为 确定这种初期的，可培养的疾病阶段。我们假设痰MTB 与MTB相比 DNA阴性/培养阴性（TB阴性）个体。为了检验这一假设，我们 启动了非洲成年人的R01资助的超诊断准确性研究 用结核病的体征/症状评估生物学和自然史超mtb dna- 积极/文化阴性个体。在AIM 1中，我们将表征主机临床和 与痰MTB DNA阳性/培养 - 阴性状态相关的人口因素 并使用预先验证的 血液转录特征可预测进展为活性结核。在AIM 2中，我们将 评估和比较MTB DNA之间结核病疾病的微生物学指标 积极/培养的否定个体和TB阴性个体。具体来说，我们建议 研究来自痰液中MTB mRNA的存在，并评估差异 从延长的孵化和培养的培养的MTB补充了生长 促进因素。最后，我们将评估MTB DNA-的自然历史 阳性/培养阴性个体相对于TB阴性对照 纵向临床，微生物学和宿主转录数据，收集在12-- 父母研究中的一个月随访期。这些拟议的研究一起将告知 超敏感的MTB DNA检测测试的实用性早期TB风险分层和 表征培养文化阴性结核病的自然史和生物标志物。