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Innate immune response of LTBI+HIV+ children

LTBI HIV 儿童的先天免疫反应

基本信息

批准号：
10263218
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
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-14 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10263218
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

项目摘要

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，造成近130万人死亡