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

HIV 阴性和阳性密切结核病接触者中活动性和初期结核病的免疫遗传学预测因素

基本信息

批准号：
10407586
负责人：
BRUNO DE BEZERRIL ANDRADE
金额：
$ 117.71万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-17 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407586
关键词：
Address Africa Antigens Bacille Calmette-Guerin vaccination Brazil CD4 Positive T Lymphocytes Cell physiology Cells Clinical Data DNA Data Development Disease Disease Progression Enrollment Epidemiologic Factors Epidemiology Future Gene Components Gene Expression Gene Expression Profile Genes Genetic Genetic Polymorphism Genomic DNA Goals Growth HIV HIV Seronegativity HIV Seropositivity Human Genetics Immune Immunity Immunogenetics Immunologic Factors Immunologics Individual Infection Innate Immune Response Interferons Knowledge Lymphocyte Function Messenger RNA Modeling Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Myeloid Cells Observation in research Pathway interactions Patients Performance Peripheral Blood Mononuclear Cell Persons Predisposing Factor Predisposition Preventive therapy Prospective Studies RNA Reporting Research Design Risk Risk Factors T cell response T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Translating Tuberculosis Tuberculosis diagnosis Vaccine Therapy Vaccines Variant Whole Blood acquired immunity analysis pipeline antigen-specific T cells antimicrobial cell type cohort epidemiologic data ethnic diversity follow-up gene discovery gene function genetic variant improved macrophage pathogen peripheral blood predictive modeling prevent prospective protective factors racial and ethnic racial diversity response sensor single cell analysis transcriptomics

项目摘要

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.

项目摘要我们小组的最新研究报告了风险（COR）转录的外周血相关性识别具有初期（无症状）结核病的个体的签名，他们发展为主动（症状） TB疾病在12个月内。我们还确定了DNA传感器基因中的人类遗传多态性巴西关闭结核病接触中与结核病风险相关的区域（pyhin1-ifi16-aim2）。 Cor和Cor pyhin1-IFI16-AIM2包括干扰素刺激的基因（ISGS）。我们假设存在免疫原性病理生理因子与初始结核和活动结核的发展有关。为了解决这个问题，我们将评估巨噬细胞中的先天免疫反应及其与人类遗传的相关多态性，对结核分枝杆菌（MTB）的免疫力以及与风险相关的流行病学因素初期和主动的结核这些研究将在区域前瞻性观察中进行结核病研究（报告） - 巴西队列，其中包括培养确认的结核病病例及其关闭大致和种族多元化的巴西接触。紧接接触2年以确定结核病的发展；大多数人没有接受或完成预防疗法，因此40种新的文化 - 预计有2,000次密切接触中的确认结核病病例将被MTB感染约45％。流行病学和临床数据，外周血单核细胞（PBMC），全血的RNA （paxgene）和基因组DNA可从基线，6个月和TB时获得所有密切接触诊断。这些免疫遗传危险因素（包括艾滋病毒）的识别将阐明宿主途径与a）对MTB的免疫相关，可以将其转化为宿主定向和疫苗疗法， b）向结核病发展 - 确定将受益于结核病预防疗法的人。