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: 10625312
• 负责人: BRUNO DE BEZERRIL ANDRADE
• 金额: $ 75.03万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625312
• 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; Macrophage; Messenger RNA; Modeling; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Myeloid Cells; Observation in research; Pathogen detection; 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; genetic variant; improved; peripheral blood; predictive modeling; prevent; prospective; protective factors; 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.

项目摘要 我们小组最近的研究报告了外周血相关风险（COR）转录 识别早期（无症状）结核病患者进展为活动性（有症状）结核病的特征 12个月内患结核病。我们还发现了人类基因多态性的DNA传感器基因 与巴西结核病密切接触者中结核病风险相关的PYHIN 1-IFI 16-AIM 2地区。COR和 PYHIN 1-IFI 16-AIM 2包括干扰素刺激基因（ISG）。我们假设有免疫遗传的 与初发TB和进展为活动性TB相关的病理生理因素。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学的相关性， 多态性，获得性免疫M。结核病（Mtb），以及与风险相关的流行病学因素 早期和活动性结核病。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，其中包括培养确诊的结核病例及其密切相关病例。 在种族和民族多元化的巴西进行接触。密切接触者随访2年，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个新的文化- 预计在2，000名密切接触者中有确诊的结核病例，其中约45%将感染结核分枝杆菌。 流行病学和临床数据，外周血单核细胞（PBMC），全血RNA （PAXgene），基因组DNA可从基线、6个月和TB时的所有密切接触者获得。 诊断.识别这些免疫遗传风险因素（包括HIV）将阐明宿主途径 与a）对Mtb的免疫力相关，其可以转化为针对宿主的疗法和疫苗疗法， 和B）发展为TB-以鉴定将受益于TB预防性治疗的人。

项目成果

Anemia and anti-tuberculosis treatment outcome in persons with pulmonary tuberculosis: A multi-center prospective cohort study.

• DOI: 10.1016/j.jiph.2023.04.009
• 发表时间: 2023-06
• 期刊: JOURNAL OF INFECTION AND PUBLIC HEALTH
• 影响因子: 6.7
• 作者: Araujo-Pereira, Mariana;Nogueira, Betania M. F.;Spener-Gomes, Renata;Carvalho, Anna C. C.;Sant'Anna, Flavia Marinho;Figueiredo, Marina C.;Turner, Megan M.;Kritski, Afranio L.;Cordeiro-Santos, Marcelo;Rolla, Valeria C.;Sterling, Timothy R.;Andrade, Bruno B.;Andrade, Alice M. S.;Nascimento, Vanessa;Cubillos-Angulo, Juan Manuel;Malta-Santos, Hayna;Reboucas-Silva, Jessica;Santos, Saulo R. N.;Ramos, Andre;Brito, Pedro;Schmaltz, Carolina A. S.;Costa, Alysson G.;Garcia, Leandro Sousa;Carvalho, Brenda K. de Sousa;Loiola, Bruna P. de;Gomes-Silva, Adriano;Ignacio, Francine P.;Lourenco, Maria C.;Silva, Elisangela C.;Mello, Mayla;Souza, Alexandra B.;Barreto-Duarte, Beatriz;Rocha, Michael S.;Benjamin, Aline;Moreira, Adriana S. R.;Oliveira, Jamile G. de;Cavalcante, Solange;Durovni, Betina;Lapa-e-Silva, Jose R.
• 通讯作者: Lapa-e-Silva, Jose R.

Determinants of losses in the tuberculosis infection cascade of care among children and adolescent contacts of pulmonary tuberculosis cases: A Brazilian multi-centre longitudinal study.

肺结核病例的儿童和青少年接触者中结核感染级联护理损失的决定因素：巴西多中心纵向研究。

• DOI: 10.1016/j.lana.2022.100358
• 发表时间: 2022
• 期刊: Lancet regional health. Americas
• 作者: Sobral,Luciana;Arriaga,MaríaB;Souza,AlexandraB;Araújo-Pereira,Mariana;Barreto-Duarte,Beatriz;Sales,Caio;Rocha,MichaelS;Benjamin,Aline;Moreira,AdrianaSR;deOliveira,JamileG;Carvalho,AnnaCristina;Spener-Gomes,Renata;Figueiredo
• 通讯作者: Figueiredo

Examination of respiratory specimens improves microbiological diagnosis of patients with presumptive extrapulmonary tuberculosis.

• DOI: 10.1016/j.ijid.2021.03.022
• 发表时间: 2021-04
• 期刊: International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases
• 作者: Spener-Gomes R;Costa AG;Melo HF;Souza AB;Beraldi-Magalhães F;Jesus JS;Arriaga MB;Kritski A;Safe I;Andrade BB;Trajman A;Cordeiro-Santos M
• 通讯作者: Cordeiro-Santos M

Influence of dietary pattern on anti-tuberculosis treatment outcomes in persons with dysglycemia: a Peruvian prospective cohort study.

• DOI: 10.3389/fnut.2023.1254983
• 发表时间: 2023
• 期刊: FRONTIERS IN NUTRITION
• 影响因子: 5
• 作者: Arriaga, Maria B.;Araujo-Pereira, Mariana;Andrade, Vanessa M. B.;Queiroz, Artur T. L.;Fernandes, Catarina D.;Sales, Caio;Aliaga, Juan Gonzalo;Shivakoti, Rupak;Lecca, Leonid;Calderon, Roger I.;Andrade, Bruno B.
• 通讯作者: Andrade, Bruno B.

Possible sex difference in latent tuberculosis infection risk among close tuberculosis contacts.

• DOI: 10.1016/j.ijid.2022.07.031
• 发表时间: 2022-09
• 期刊: INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES
• 影响因子: 8.4
• 作者: Wada, Paul Y.;Costa, Allyson G.;Araujo-Pereira, Mariana;Barreto-Duarte, Beatriz;Souza, Alexandra B.;Rocha, Michael S.;Figueiredo, Marina C.;Turner, Megan M.;Rolla, Valeria C.;Kritski, Afranio L.;Cordeiro-Santos, Marcelo;Andrade, Bruno B.;Sterling, Timothy R.;Rebeiro, Peter F.
• 通讯作者: Rebeiro, Peter F.