Innate immune response of LTBI+HIV+ children

LTBI HIV 儿童的先天免疫反应

• 批准号: 10470320
• 负责人: Ramakrishna Vankayalapati
• 金额: $ 69.51万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470320
• 关键词: Adult; Age; Antitubercular Agents; Blood specimen; CD8-Positive T-Lymphocytes; Cause of Death; Cells; Cellular Immunity; Cessation of life; Child; Defect; Development; FOXP3 gene; Family; Future; Genetic Polymorphism; Growth; HIV; HIV Infections; HIV/TB; Haplotypes; Highly Active Antiretroviral Therapy; Household; Human; IL2RA gene; Immune; Immune response; Immune system; Immunity; Immunoglobulins; India; Individual; Infection; Innate Immune Response; Investments; Killer Cells; Measures; Mediating; Memory; Mus; Mycobacterium tuberculosis; Natural Killer Cells; Nature; Patients; Persons; Phenotype; Play; Population; Predisposition; Production; Prophylactic treatment; Publishing; Reporting; Research; Research Personnel; Resistance; Response Latencies; Risk; Role; Sampling; Series; Site; T cell response; Time; Tuberculosis; Tuberculosis Vaccines; Vaccines; adaptive immune response; base; cell mediated immune response; chemokine; cohort; cytokine; high risk; individual response; macrophage; monocyte; novel; pediatric patients; prevent; receptor; response

Mycobacterium tuberculosis (Mtb) infects one-third of the world’s population and causes almost 1.3 million deaths per year, including 100, 000 children. Approximately 90% of infected persons have latent tuberculosis infection (LTBI), have protective immunity and remain well, but 10% develop primary tuberculosis (TB) soon after infection or reactivation TB many years later. Children are more susceptible to TB infection, due to an immature immune system. HIV infection in children markedly increases susceptibility to TB, and HIV-infected persons with LTBI have an 800-fold greater risk of developing active TB (www.cdc.gov/tb/). TB is the leading cause of death in HIV-infected persons and more than half a million coinfected people die annually. To develop adequate prophylaxis or therapy, it is important to understand immune responses to Mtb. Identification of HIV+ children with LTBI who are at greatly increased risk for development of TB would allow treating only high-risk children, facilitating completion of therapy for LTBI and preventing future development of TB. To identify these children, it is important to pinpoint the nature of the defective immune responses that permit development of active TB in HIV+LTBI+ pediatric patients. Over the past 18 years, we have published a series of articles demonstrating that human NK cells have the potential to contribute to both innate and adaptive immune responses to Mtb. Our recently published studies demonstrate that memory-like NK cells contribute to vaccine-induced protective immunity against Mtb and IL-21 is required for expansion of memory-like NK cells in both humans and mice. Based on our published studies, we hypothesize that HIV-LTBI+ children household contacts have defective memory-like NK cell expansion compared to HIV-LTBI+ adult household contacts and these defects are more severe in HIV+ LTBI+ children. The proposed studies in the current application will be performed in India as a part of RePORT-India consortium. This study will leverage the large Indo-US investment and TB/HIV research consortium of RePORT-India which has developed cohorts of TB cases and household contacts in India and has paired Indian investigators with US investigators at 6 sites. Already collected samples will be used for the proposed studies in aim 1. Our specific aims are: 1. Determine Mtb specific memory-like NK cell responses of children in a large group of household contacts of TB patients. 2.Compare the memory-like NK cell responses of HIV+ and HIV- children with LTBI. 3. Determine whether KIR haplotypes and HLA polymorphism is associated with expansion of memory-like NK cells in children.

结核分枝杆菌 (Mtb) 感染了世界三分之一的人口，导致近 130 万人死亡 每年死亡人数，其中包括 100, 000 名儿童。大约90%的感染者有潜伏性结核病 感染 (LTBI)，具有保护性免疫力并保持良好状态，但 10% 很快会发展为原发性结核病 (TB) 感染或结核病多年后重新激活后。儿童更容易感染结核病，因为 免疫系统不成熟。儿童感染艾滋病毒显着增加结核病的易感性，而艾滋病毒感染者 患有 LTBI 的人患活动性结核病的风险要高出 800 倍 (www.cdc.gov/tb/)。结核病是主导 是艾滋病毒感染者的死因，每年有超过 50 万同时感染者死亡。发展 充分的预防或治疗，了解 Mtb 的免疫反应非常重要。 HIV+ 的识别 患有 LTBI 的儿童患结核病的风险大大增加，因此只能接受高风险治疗 儿童，促进 LTBI 治疗的完成并预防结核病的未来发展。为了识别这些 对于儿童来说，重要的是要查明有缺陷的免疫反应的性质，这些反应会导致儿童的发育 HIV+LTBI+儿童患者的活动性结核病。 在过去的 18 年里，我们发表了一系列文章，证明人类 NK 细胞已经 有助于对结核分枝杆菌的先天性和适应性免疫反应的潜力。我们最近发布的 研究表明，记忆样 NK 细胞有助于疫苗诱导的针对 Mtb 的保护性免疫 人类和小鼠的记忆样 NK 细胞的扩增都需要 IL-21。基于我们的 已发表的研究中，我们假设 HIV-LTBI+ 儿童的家庭接触者有缺陷 与 HIV-LTBI+ 成年家庭接触者相比，NK 细胞具有记忆样扩张，这些缺陷 HIV+ LTBI+ 儿童中情况更为严重。当前申请中拟议的研究将在 印度作为RePORT-India 联盟的一部分。这项研究将利用印美两国的大量投资和结核病/艾滋病毒 印度报告研究联盟开发了结核病病例和家庭接触者队列 印度并已在 6 个地点将印度调查人员与美国调查人员配对。已经采集的样本将被 用于目标 1 中提出的研究。我们的具体目标是： 1. 确定 Mtb 特异性记忆样 NK 细胞 大量结核病患者家庭接触者中儿童的反应。 2.对比类记忆NK 患有 LTBI 的 HIV+ 和 HIV- 儿童的细胞反应。 3. 确定KIR单倍型和HLA是否一致 多态性与儿童记忆样 NK 细胞的扩张有关。