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

• 批准号: 10380637
• 负责人: Deepak Kaushal
• 金额: $ 155.86万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380637
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Aerosols; Age; Age-Months; Animals; Antigens; Attenuated; BCG Vaccine; Birth; Blood; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cause of Death; Cessation of life; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Clinical; Communicable Diseases; Country; Development; Disease; Disease Progression; Dose; Emergency Situation; Epidemic; Epidemiology; Exposure to; Failure; Frequencies; Generations; Goals; HIV; HIV Infections; HIV/TB; Immune; Immune System Diseases; Immune response; Immune system; Immunologics; Immunology; Immunotherapy; Impairment; Incidence; Individual; Infant; Infection; Intervention; Lung; Lymphocyte; Lymphoid Cell; Macaca; Meningitis; Miliary Tuberculosis; Modeling; Monitor; Morbidity - disease rate; Mucosal Immune System; Mucous Membrane; Mycobacterium Infections; Mycobacterium bovis; Mycobacterium tuberculosis; Neonatal; Newborn Infant; Outcome; Pathogenesis; Pathologic; Pathology; Patients; Perinatal; Postpartum Period; Predisposition; Prevention strategy; Primates; Principal Investigator; Process; Public Health; Pulmonary Pathology; Pulmonary Tuberculosis; Regulatory T-Lymphocyte; Research; Resources; Risk; SIV; Sampling; Severities; Severity of illness; System; T cell response; T-Lymphocyte Subsets; Tissues; Treatment Efficacy; Tuberculosis; Viral; Viral reservoir; Virus Diseases; Woman; age related; antiretroviral therapy; base; co-infection; cohort; design; driving force; immune function; immune reconstitution; immune system function; in utero; infant infection; inhibitor; insight; intrapartum; lymph nodes; lymphocyte proliferation; macrophage; mortality; mycobacterial; neonatal immune system; neonatal immunity; neonatal infection; nonhuman primate; pathogen; pediatric human immunodeficiency virus; perinatal period; preservation; prevent; response; restoration; synergism; treatment response; treatment strategy; tuberculosis immunity

Principal Investigators (Last, first, middle): Wang, Xiaolei & Kaushal, Deepak 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-

首席调查员（最后，第一，中间）：王，小和考沙尔，迪帕克 项目摘要/摘要： 结核病（TB）是人类免疫缺陷病毒/获得性免疫缺乏的主要原因 综合征（HIV/AIDS）全球患者，对于婴儿而言尤其如此。虽然研究有 揭示了HIV/MTB共同感染的成年人病理变化的某些方面，对 具有治疗策略在艾滋病毒相关的MTB感染中的发病机理和功效 开发免疫系统，增加了其对某些传染病的脆弱性。最近的进步 对新生儿免疫力的理解表明，先天和适应性反应都取决于 淋巴细胞，抗原剂量和暴露方式的前体频率。小儿艾滋病毒的临床课程 已经揭示了在免疫发育的关键窗口中发生围产期获得的HIV感染，并且 艾滋病毒对这种动态过程的扰动可能解释 疾病进展。幼儿中的结核病通常是无法察觉的，并且可以迅速发展为活动疾病， 但是MTB对婴儿发展的免疫系统的影响本质上是未知的。因此，更好 了解小儿宿主中与HIV相关的MTB感染的免疫发病发生对于 提供适当的干预措施，可以降低与共同感染的婴儿发病率和死亡率的风险 艾滋病毒和mtb。我们一直在使用非人类灵长类动物模型来研究新生儿免疫学，并显示 新生儿免疫系统高度分室，具有更高的粘膜免疫 系统比出生时的系统系统和小儿SIV感染导致发展受损和 新生儿粘膜和全身免疫系统的功能。该建议旨在确定 SIV感染引起的免疫变化导致婴儿MTB严重程度增加， 以及早期抗逆转录病毒疗法（ART）和免疫疗法（IDO抑制剂治疗）的影响 通过比较病毒/细菌负担，先天性，自适应和病原体特异性细胞和体液来感染 免疫反应，肺病理，潜伏期，储层和疾病进展。我们的目标 研究是：a）表征MTB对全身和粘膜发展和成熟的影响 婴儿猕猴的免疫系统，无论是否接受免疫疗法； b）比较免疫反应和 SIV/MTB共感染的婴儿猕猴的病理； c）确定是否早期开始艺术的开始 随后的免疫疗法降低了婴儿与HIV相关的MTB感染中的发病率和死亡率。经过 使用全面和多收益的方法来定义MTB感染对发展的影响 免疫系统的功能，并识别MTB特异性免疫恢复的基础机制 在感染SIV的婴儿中的功能，我们的研究将提高我们对结核病免疫发病的理解 在艾滋病毒感染的儿童中，这可能会提供有关可以针对的免疫机制的新见解 与MTB共同感染的婴儿更有效的预防和治疗策略。 -1-