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的检测和治疗。 疾病。在结核病高负担导致高负担的地区，这种方法的有效性可能有限 传播水平。为了遏制结核病的流行，必须预防新的病例。预防性治疗是一种 有效的干预措施，因为它将艾滋病毒阳性(HIV+)患者进展为疾病的风险降低了65%-85% 和阴性(艾滋病毒携带者)。一个巨大的挑战仍然存在：世界上四分之一的人口 感染结核分枝杆菌。对所有患有LTBI的人进行治疗是不可行的：一种确定哪些人处于最高风险的策略 需要进展为结核病。新感染的接触者经历了一段进展性的高危时期 持续约2至3年的疾病。我们最近在乌干达城市进行的队列研究测量了结核分枝杆菌的年发病率 社区感染率接近10%/年。对于大多数结核分枝杆菌潜伏感染(LTBI)的人来说， 感染的可能性尚不清楚，最近感染的生物标记物将有助于识别患有 疾病的发展。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)确定了新的结核分枝杆菌感染的蛋白质特征。改进此签名，并 确定它在社区中的使用来识别最近患上LTBI的人将允许有针对性的 预防性治疗和“阻止结核分枝杆菌的传播”。这一提议的总体假设是血清/血浆 新结核分枝杆菌感染的生物标志物特征可以识别结核分枝杆菌高传播区的HIV+和HIV-成人 以这些人为目标进行预防性治疗将减少结核病和结核杆菌在社区中的传播。 有三个目标。目标1将测试和增强宿主蛋白签名作为新的结核分枝杆菌感染的生物标记物 艾滋病毒感染者和非感染者。我们将使用正在进行的结核病家庭接触者中收集的血浆 在乌干达坎帕拉进行的一项研究，该研究登记了TST-/IGRA-HIV+和HIV-成年人，并跟踪了IGRA/TST 转换。我们将确定血清细胞因子是否能提高这一蛋白质信号的预测准确性。 目标2将在非洲城市环境的高危环境中确定新的结核分枝杆菌感染情况。GPS跟踪 将使用技术来追踪和纵向绘制受试者的地图，以定位结核分枝杆菌高传播区，即 “热点”。受试者将在1年内每3个月登记并跟踪IGRA/TST转换 对血浆进行连续采样。目标3将确定在目标1中开发的蛋白质特征码(S)是否能够识别新的 社区中的结核分枝杆菌感染。这个项目建立在20多年的经验基础上，通过这次调查 研究结核分枝杆菌在乌干达坎帕拉家庭和社区中传播的小组，以及宿主对 HIV+和HIV感染者中的结核杆菌感染和疾病。该提案汇集了Mtb的专业知识。 流行病学(Whalen、Kiwanuka、Joloba、Stein博士)、免疫学(Mayanja博士、Boom博士)和生物标记物 CWRU、Makerere大学、佐治亚大学和Caprion Inc.的发展(Bark博士，Paramithiotis)。

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.