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

• 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
• 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

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.

项目总结