Innate immune response of LTBI+HIV+ children

结核分枝杆菌（Mtb）感染了世界三分之一的人口， 包括10万名儿童。大约90%的感染者患有潜伏性结核病 感染（LTBI），有保护性免疫力，并保持良好，但10%发展为原发性结核病（TB）很快 感染或多年后结核病复发。由于结核病的影响，儿童更容易感染结核病 不成熟的免疫系统儿童艾滋病毒感染显著增加了对结核病的易感性， LTBI患者患活动性结核病的风险高800倍（www.cdc.gov/tb/）。结核病是主要的 这是艾滋病毒感染者死亡的主要原因，每年有50多万合并感染者死亡。发展 为了获得足够的预防或治疗，重要的是了解对Mtb的免疫应答。HIV+的识别 患有LTBI的儿童患结核病的风险大大增加， 儿童，促进LTBI治疗的完成，并预防未来结核病的发展。识别这些 儿童，重要的是要查明允许发展的缺陷免疫反应的性质， HIV+LTBI+儿科患者中的活动性结核病。 在过去的18年里，我们发表了一系列文章，证明人类NK细胞具有 有助于对Mtb的先天性和适应性免疫应答的潜力。我们最近出版的 研究表明，记忆样NK细胞有助于疫苗诱导的抗Mtb保护性免疫 IL-21是人类和小鼠记忆样NK细胞扩增所必需的。基于我们 发表的研究，我们假设HIV-LTBI+儿童家庭接触有缺陷， 与HIV-LTBI+成人家庭接触者相比，记忆样NK细胞扩增，这些缺陷是 在HIV+ LTBI+儿童中更严重。本申请中的拟定研究将在 印度作为报告印度财团的一部分。这项研究将利用印度-美国的大量投资和结核病/艾滋病毒 印度报告研究联盟，该研究联盟在印度开发了结核病例和家庭接触者队列， 印度，并在6个研究中心将印度研究人员与美国研究人员配对。已经采集的样本将 用于目标1中拟议的研究。我们的具体目标是：1.确定Mtb特异性记忆样NK细胞 在结核病患者的家庭接触的一大群儿童的反应。2.比较记忆类NK HIV+和HIV-儿童LTBI的细胞反应。3.确定KIR单倍型和HLA 多态性与儿童记忆样NK细胞的扩增相关。

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.