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Impact of tuberculosis on the development and function of the immune system in SIV-infected infants

结核病对 SIV 感染婴儿免疫系统发育和功能的影响

基本信息

批准号：
10444441
负责人：
Deepak Kaushal
金额：
$ 46.62万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
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：
2021-09-17 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10444441
关键词：
Acquired Immunodeficiency Syndrome Adult Animals Biopsy Birth CD4 Positive T Lymphocytes Cause of Death Cessation of life Child Childhood Childhood Acute Lymphocytic Leukemia Chronic Clinical Communicable Diseases Country DNA DNA Integration Development Disease Disease Progression Disease remission Dose Drug Combinations Early treatment Enzymes Epidemic Epidemiology Event Failure Frequencies HIV HIV Infections HIV/TB Hour Immune Immune response Immune system Immunity Immunologics Immunology Immunotherapy Impairment In complete remission Incidence Individual Infant Infection Integrase Integrase Inhibitors Interruption Intervention Intravenous Life Cycle Stages Literature Lymphocyte Lymphoid Tissue Macaca Measures Modeling Morbidity - disease rate Mucosal Immune System Mucous Membrane Mycobacterium tuberculosis Neonatal Newborn Infant Outcome Pathogenesis Pathologic Pathology Patients Perinatal Pharmaceutical Preparations Prevention strategy Process Production Proviruses Public Health Pulmonary Pathology Regimen Reporting Research Residual state Resources Risk SIV Severities System T-Cell Depletion T-Lymphocyte Therapeutic Time Tissues Treatment Efficacy Treatment Protocols Tuberculosis Viral Viral reservoir Viremia Virus Virus Integration Woman age related antiretroviral therapy cohort design driving force immune function immune system function improved infant infection inhibitor/antagonist insight microbial mortality neonatal immune system neonatal immunity neonatal infection neonate nonhuman primate parent grant pathogen pediatric human immunodeficiency virus preservation prevent rectal response restoration synergism treatment optimization treatment strategy viral DNA viral rebound virology

项目摘要

PROJECT SUMMARY/ABSTRACT: Tuberculosis (TB) is the leading cause of death in Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) patients worldwide, and this is particularly true for infants. Although studies have disclosed some aspects of pathological changes in HIV/Mtb co-infected adults, very little is known about the pathogenesis and efficacy of therapeutic strategies in HIV-associated Mtb infection in infants, who possess a developing immune system that increases their vulnerability to certain infectious diseases. Recent advances in understanding of neonatal immunity indicate that both innate and adaptive responses are dependent on precursor frequencies of lymphocytes, antigenic dose, and mode of exposure. Clinical course of pediatric HIV has revealed perinatally acquired HIV infection occurs during a critical window of immune development, and HIV’s perturbation of this dynamic process may account for the striking age-dependent differences in HIV disease progression. TB in young children is often imperceptible and can rapidly progress to active disease, but the effects of Mtb on the developing immune system of infants is essentially unknown. Therefore, a better understanding of the immunopathogenesis of HIV-associated Mtb infection in pediatric hosts is essential to provide appropriate interventions, which can reduce risk of morbidity and mortality in infants co-infected with HIV and Mtb. We have been using nonhuman primate models to study neonatal immunology and have shown the neonatal immune system is highly compartmentalized, with a much more competent mucosal immune system than the systemic system at birth, and pediatric SIV infection results in impaired development and function of the neonatal mucosal and systemic immune systems. This proposal is designed to determine the immunological changes induced by SIV infection that contributes to the increased severity of Mtb in infants, and the effects of early antiretroviral therapy (ART) and immunotherapy (IDO-inhibitor treatment) on both infections by comparing viral/bacterial burdens, innate, adaptive, and pathogen specific cellular and humoral immune responses, pulmonary pathology, latency, reservoirs, and disease progression. The objectives of our studies are to: a) characterize the effects of Mtb on the development and maturation of systemic and mucosal immune systems in infant macaques that with or without immunotherapy; b) compare immune responses and pathology in SIV/Mtb co-infected infant macaques; and c) determine whether early initiation of ART with subsequent immunotherapy reduces morbidity and mortality among HIV-associated Mtb infection in infants. By using a comprehensive and multipronged approach to define the impacts of Mtb infection on the development and function of the immune system, and identifying mechanisms underlying restoration of Mtb-specific immune function in SIV-infected infants, our studies will advance our understandings of the immunopathogenesis of TB in HIV-infected children, which may provide new insights into immune mechanisms that can be targeted for more effective prevention and treatment strategies for infants co-infected with Mtb. -1-

项目总结/文摘: