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The effect of HIV exposure and infection on immunity to TB in children

HIV暴露和感染对儿童结核病免疫力的影响

基本信息

批准号：
10535514
负责人：
Cheryl Liane Day
金额：
$ 7.06万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-10 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10535514
关键词：
Activities of Daily Living Address Adult Aggressive course Bacille Calmette-Guerin vaccination CD4 Positive T Lymphocytes Cells Cessation of life Characteristics Child Childhood Chromatin Clinical Cohort Studies Cryopreservation DNA Data Development Disease Epigenetic Process Genus Mycobacterium HIV HIV Infections HIV antiretroviral HIV/TB Heterochromatin High Prevalence Immune Immune response Immunity Immunize Infant Infant Mortality Infection Inflammatory Response Pathway Innate Immune Response Kenya Life Longitudinal cohort Mediating Morbidity - disease rate Mycobacterium tuberculosis Natural Killer Cells Neonatal Neonatal Mortality Newborn Infant Pediatric cohort Peripheral Blood Mononuclear Cell Phenotype Populations at Risk Predisposition Prevalence Reporting Risk Site Specimen Technology Testing Training Tuberculosis Umbilical Cord Blood Vaccination Virus adaptive immune response antiretroviral therapy co-infection cofactor cohort epigenome infant infection infection risk insight monocyte mortality mycobacterial novel pathogen pathogenic bacteria pathogenic fungus pathogenic virus pediatric human immunodeficiency virus prenatal exposure preventive intervention repository response transcriptome tuberculosis immunity

项目摘要

Project Summary / Abstract Over one million new cases of tuberculosis (TB) and 239,000 TB-related deaths occur in children each year. Despite evidence that HIV exposure in children is associated with a markedly increased risk of infection with Mycobacterium tuberculosis (Mtb) and development of TB disease, few studies have explored mechanisms for HIV-related susceptibility to TB in children. HIV-exposed uninfected children (HEU) are exposed in utero to both maternal HIV and anti-retroviral therapy (ART) and these exposures may influence subsequent immune responses to Mtb. In settings with high prevalence of HIV and TB, newborns typically receive BCG vaccination within the first few days of life, which confers some protection against severe forms of TB in young children. Interestingly, BCG vaccination has also been recognized to confer non-specific beneficial effects, including reduced neonatal and infant mortality. Moreover, vaccination with BCG is associated with enhanced innate immune responses to mycobacteria as well as heterologous pathogens, a phenomenon termed “trained immunity”. Epigenetic reprogramming of innate immune cells, including monocytes and NK cells, is one mechanism identified that contributes to BCG-induced trained immunity. The effect of maternal HIV exposure and infant HIV infection on induction of trained immunity to Mtb in BCG-vaccinated infants has not been described. Our studies will characterize innate and adaptive immune responses to mycobacteria, cofactors such as ART that may influence immune responses, and the implications of these immune responses for susceptibility to pediatric Mtb infection. We will test the hypotheses that (1) maternal HIV exposure and infant HIV infection dampen induction of trained immunity to Mtb via epigenetic reprogramming of innate immune cells in BCG-vaccinated infants; and (2) ART enhances innate and adaptive anti-mycobacterial immune responses in HIV-infected children and that deficits in anti-mycobacterial immunity will predict acquisition of Mtb infection. Using clinically-well characterized longitudinal cohorts of infants and children in Kenya, we will perform a comprehensive analysis of the phenotype, function, epigenome and transcriptome of innate immune responses in HEU, HIV-infected, and HIV-unexposed uninfected infants. We will then determine the capacity of ART to restore innate and adaptive anti-mycobacterial immune responses in HIV-infected children and identify immune correlates that predict acquisition of Mtb infection. These studies will provide unprecedented insights into mechanisms of HIV-associated modulation of immunity to Mtb in infants and children and will inform novel TB preventive interventions in these at-risk populations.

项目摘要/摘要