Immunogenetic predictors of active and incipient TB in HIV-negative and -positive close TB contacts

项目总结 我们小组最近的研究报告了一种外周血风险相关(COR)转录 识别早期(无症状)结核病患者进展为活动期(有症状)的签名 12个月内罹患结核病。我们还发现了DNA感应器基因中的人类遗传多态。 巴西密切结核病接触者中与结核病风险相关的区域(PYHIN1-IFI16-AIM2)。COR和COR PYHIN1-IFI16-AIM2包括干扰素刺激基因(ISGs)。我们假设有免疫遗传 与早期结核病和进展为活动性结核病相关的病理生理学因素。为了解决这个问题， 我们将评估巨噬细胞的先天免疫反应及其与人类遗传的相关性 多态、对结核分枝杆菌获得性免疫(Mtb)和与风险相关的流行病学因素 初发期和活动性结核病。这些研究将在区域前瞻性观测中进行 结核病研究(报告)--巴西队列，包括经培养确认的结核病病例及其近亲 在种族和民族多元化的巴西的联系人。对密切接触者进行为期两年的跟踪调查，以确定 结核病的发展；大多数人没有接受或完成预防性治疗，因此40种新文化-- 在2000名密切接触者中，预计将有确诊结核病病例，其中约45%将感染结核分枝杆菌。 流行病学和临床资料，外周血单个核细胞(PBMC)，全血RNA (PAX基因)和基因组DNA可从所有密切接触者在基线、6个月和结核病时获得 诊断。识别这些免疫遗传危险因素(包括艾滋病毒)将有助于阐明宿主的途径。 与a)对结核分枝杆菌的免疫有关，这可以转化为宿主导向和疫苗疗法， 以及b)进展为结核病--以确定将从结核病预防治疗中受益的人。

PROJECT SUMMARY Recent studies from our group have reported a peripheral blood correlate of risk (COR) transcriptional signature that identified individuals with incipient (asymptomatic) TB who progressed to active (symptomatic) TB disease within 12 months. We have also identified human genetic polymorphisms in a DNA sensor gene region (PYHIN1-IFI16-AIM2) associated with TB risk in Brazilian close TB contacts. Both the COR and PYHIN1-IFI16-AIM2 include interferon stimulated genes (ISGs). We hypothesize that there are immunogenetic pathophysiologic factors associated with incipient TB and progression to active TB. To address this question, we will evaluate innate immune responses in macrophages and their correlates with human genetic polymorphisms, acquired immunity to M. tuberculosis (Mtb), and epidemiologic factors associated with the risk of incipient and active TB. These studies will be performed in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort, which includes culture-confirmed TB cases and their close contacts in racially and ethnically diverse Brazil. Close contacts are followed for 2 years to identify development of TB disease; most persons do not receive or complete preventive therapy, so 40 new culture- confirmed TB cases are expected among 2,000 close contacts, ~45% of whom will be infected with Mtb. Epidemiologic and clinical data, peripheral blood mononuclear cells (PBMC), RNA from whole blood (PAXgene), and genomic DNA are available from all close contacts at baseline, 6 months, and at TB diagnosis. Identification of these immunogenetic risk factors (including HIV) will illuminate host pathways associated with both a) immunity to Mtb, which could be translated into host-directed and vaccine therapies, and b) progression to TB—to identify persons who would benefit from TB preventive therapy.