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

项目摘要/摘要： 结核病(TB)是人类免疫缺陷病毒/获得性免疫缺陷的主要死亡原因 世界各地都有艾滋病毒/艾滋病综合症患者，婴儿尤其如此。尽管研究表明 揭示了HIV/结核分枝杆菌混合感染成人的某些方面的病理变化，对 婴儿HIV相关结核分枝杆菌感染的发病机制和治疗策略 发展免疫系统，增加他们对某些传染病的易感性。的最新进展 对新生儿免疫的了解表明，先天和适应性反应都依赖于 淋巴细胞前体频率、抗原剂量和暴露方式。儿童HIV的临床病程 揭示了围产期获得性艾滋病毒感染发生在免疫发育的关键时期，以及 HIV对这一动态过程的扰动可能解释了HIV在年龄上的显著差异 疾病的发展。幼儿中的结核病通常是难以察觉的，并可能迅速发展为活动性疾病， 但结核分枝杆菌对婴儿发育中的免疫系统的影响基本上是未知的。因此，一个更好的 了解儿童宿主中HIV相关结核分枝杆菌感染的免疫发病机制对于 提供适当的干预措施，可降低合并感染疟疾的婴儿的发病率和死亡率 HIV和结核分枝杆菌。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，并表明 新生儿免疫系统高度区隔，具有更强的粘膜免疫能力。 出生时的系统比出生时的系统要好，儿科SIV感染会导致发育受损和 新生儿粘膜和全身免疫系统的功能。本提案旨在确定 SIV感染引起的免疫学变化导致婴儿结核分枝杆菌的严重程度增加， 早期抗逆转录病毒治疗(ART)和免疫治疗(IDO抑制剂治疗)对两者的影响 通过比较病毒/细菌负担、先天的、适应性的和病原体特定的细胞和体液感染 免疫反应、肺部病理、潜伏期、蓄水池和疾病进展。我们的目标是 研究目的：a)确定结核分枝杆菌对全身和粘膜发育和成熟的影响。 婴儿猕猴的免疫系统，无论是否接受免疫治疗；b)比较免疫反应和 SIV/结核分枝杆菌混合感染的婴儿猕猴的病理学；以及c)确定早期启动抗逆转录病毒治疗是否与 随后的免疫治疗降低了婴儿中艾滋病毒相关结核分枝杆菌感染的发病率和死亡率。通过 采用全面和多管齐下的方法，确定结核分枝杆菌感染对发展的影响 和免疫系统的功能，以及确定结核分枝杆菌特异性免疫恢复的潜在机制 在SIV感染婴儿中的作用，我们的研究将促进我们对结核病免疫发病机制的理解 在感染艾滋病毒的儿童中，这可能为研究免疫机制提供新的见解 对合并感染结核杆菌的婴儿采取更有效的预防和治疗策略。 -1-

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-