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

项目总结/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因 艾滋病病毒/艾滋病综合征（艾滋病毒/艾滋病）患者的死亡率在全球范围内呈上升趋势，婴儿尤其如此。虽然研究 公开了HIV/Mtb共感染成人中病理变化的一些方面，但对HIV/Mtb共感染成人的病理变化知之甚少。 在婴儿中HIV相关Mtb感染的发病机制和治疗策略的有效性， 发展免疫系统，增加他们对某些传染病的脆弱性。的最新进展 对新生儿免疫的理解表明，先天性和适应性反应都依赖于 淋巴细胞的前体频率、抗原剂量和暴露方式。儿童HIV临床病程 已经揭示围产期获得性HIV感染发生在免疫发育的关键窗口期， 艾滋病毒对这一动态过程的干扰可能解释了艾滋病毒中显著的年龄依赖性差异 疾病进展。幼儿结核病通常不易察觉，可迅速发展为活动性疾病， 但结核分枝杆菌对婴儿免疫系统发育的影响基本上是未知的。因此，更好的 了解儿童宿主中HIV相关Mtb感染的免疫发病机制， 提供适当的干预措施，减少同时感染 艾滋病毒和结核病。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，并已表明 新生儿的免疫系统是高度区室化的，具有更强的粘膜免疫能力。 系统比出生时的全身系统，儿科SIV感染导致发育受损， 新生儿粘膜和全身免疫系统的功能。该提案旨在确定 SIV感染诱导的免疫学变化导致婴儿Mtb严重程度增加， 以及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/细菌负荷、先天性、适应性和病原体特异性细胞和体液 免疫反应、肺部病理、潜伏期、储库和疾病进展。我们的目标 研究的目的是：a）表征Mtb对全身和粘膜的发育和成熟的影响， 在有或没有免疫治疗的情况下，婴儿猕猴的免疫系统; B）比较免疫应答， 在SIV/Mtb共感染的幼年猕猴中的病理学;和c）确定是否早期开始ART， 随后的免疫治疗降低了婴儿中HIV相关Mtb感染的发病率和死亡率。通过 采用全面和多管齐下的方法来确定结核病感染对发展的影响， 和功能的免疫系统，并确定机制的恢复结核特异性免疫 在SIV感染的婴儿中的功能，我们的研究将促进我们对结核病免疫发病机制的理解 这可能为免疫机制提供新的见解， 对合并感染结核分枝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-