Capturing spatial patterns of new M. tuberculosis infection in Kampala, Uganda

摘要 结核病控制的标准方法依赖于结核分枝杆菌（Mtb）的检测和治疗 疾病这种方法在结核病高负担导致高死亡率的地区可能效果有限。 传输的水平。为了遏制结核病的流行，必须防止新的病例。预防性治疗是一种 有效的干预措施，因为它降低了65 - 85%的艾滋病毒阳性（艾滋病毒+） 和阴性（HIV-）个体。一个巨大的挑战仍然存在：世界人口的四分之一是 感染了Mtb。治疗所有LTBI患者是不可行的：一种识别最高风险人群的策略 需要发展为结核病。新感染的接触者经历了一段进行性感染的高风险时期。 我们最近在乌干达城市进行的队列研究测量了结核病的年发病率， 社区感染率接近10%/年。对于大多数潜伏性Mtb感染（LTBI）的个体， 感染的风险尚不清楚，最近感染的生物标志物将有助于确定最有可能感染的人。 疾病进展。结核病家庭接触者血清蛋白质组学分析 结核菌素皮肤试验（TST）鉴定了新的Mtb感染的蛋白质特征。在这个签名的基础上， 确定其在社区中的使用，以确定最近开发LTBI的人将允许有针对性地 预防性治疗和“停止结核病传播”。该提议的总体假设是血清/血浆 新的Mtb感染的生物标志物特征可以识别Mtb高传播地区的HIV+和HIV-成人 针对这些人进行预防性治疗将减少结核病和结核分枝杆菌在社区的传播。 有三个目标。目标1将测试和增强宿主蛋白质特征作为新的结核分枝杆菌感染的生物标志物， 艾滋病毒感染者和非感染者。我们将使用在正在进行的结核病家庭接触中收集的血浆 在乌干达坎帕拉进行的一项研究，其中入组了TST-/IGRA- HIV+和HIV-成人，并进行了IGRA/TST随访 转换.我们将确定血清细胞因子是否能提高这种蛋白质特征的预测准确性。 目标2将确定非洲城市环境中高风险环境中新的结核分枝杆菌感染。GPS跟踪 技术将用于追踪和纵向绘制受试者的地图，以确定结核病高传播地区，即 “热点”。受试者将入组并在1年内每3个月随访一次IGRA/TST转换， 血浆的连续采样。目标3将确定目标1中开发的蛋白质特征是否可以识别新的 社区结核病感染。这个项目建立在20多年的经验，由这个调查 研究乌干达坎帕拉结核病家庭和社区中结核病传播情况的小组， HIV+和HIV-人群中的结核分枝杆菌感染和疾病。该提案汇集了结核病方面的专业知识， 流行病学（Whalen、Kiwanuka、Joloba、Stein博士）、免疫学（Mayanja、Boom博士）和生物标志物 开发（Bark，Paramithiotis博士）在CWRU，Makerere大学，格鲁吉亚大学和Caprion公司。

Abstract The standard approach to TB control relies on detection and treatment of Mycobacterium tuberculosis (Mtb) disease. This approach may have limited effectiveness in areas where the high burden of TB leads to high levels of transmission. To curb the TB epidemic, new cases must be prevented. Preventive therapy is an effective intervention as it reduces the risk of progression to disease by 65 – 85% in both HIV-positive (HIV+) and negative (HIV-) individuals. A monumental challenge still remains: one-quarter of the world's population is infected with Mtb. Treating all individuals with LTBI is not feasible: a strategy to identify those at highest risk for progression to TB is required. Contacts who are newly infected experience a period of high risk for progressive disease that lasts about 2 to 3 yrs. Our recent cohort study in urban Uganda measured the annual rate of Mtb infection in the community as close to 10%/yr. For most individuals with latent Mtb infection (LTBI), the timing of infection is unknown and biomarkers of recent infection would help identify persons at greatest risk for disease progression. A proteomic analysis of serum from TB household contacts who converted their tuberculin skin test (TST) identified a protein signature for new Mtb infection. Improving upon this signature and determining its use in the community to identify persons who recently developed LTBI would allow for targeted preventive therapy and “halt Mtb transmission”. The overall hypothesis for this proposal is that serum/plasma biomarker signatures of new Mtb infection can identify HIV+ and HIV- adults in high Mtb transmission areas and targeting these individuals for preventive therapy will reduce TB and Mtb transmission in the community. There are 3 aims. Aim 1 will test and enhance a host protein signature as biomarker for new Mtb infection in HIV-infected and non-infected persons. We will use plasma collected in an ongoing TB household contact study in Kampala, Uganda in which TST-/IGRA- HIV+ and HIV- adults are enrolled and followed for IGRA/TST conversion. We will determine if serum cytokines enhance the predictive accuracy of this protein signature. Aim 2 will identify new Mtb infection in high risk environments in an urban African setting. GPS tracking technology will be used to trace and longitudinally map subjects to locate areas of high Mtb transmission, i.e. “hot-spots”. Subjects will be enrolled and followed for IGRA/TST conversion every 3 months over 1 yr with serial sampling of plasma. Aim 3 will determine if the protein signature(s) developed in Aim 1 can identify new Mtb infections in the community. This project builds on more than 20 years of experience by this investigative team studying Mtb transmission in TB households and community in Kampala, Uganda, and host responses to Mtb infection and disease in HIV+ and HIV- persons. This proposal brings together expertise in Mtb epidemiology (Drs. Whalen, Kiwanuka, Joloba, Stein), immunology (Drs. Mayanja, Boom) and biomarker development (Drs. Bark, Paramithiotis) at CWRU, Makerere University, University of Georgia, and Caprion Inc.