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/获得性免疫缺陷导致死亡的主要原因 全世界都有艾滋病毒/艾滋病（HIV/AIDS）患者，尤其是婴儿。尽管研究已 揭示了 HIV/Mtb 共同感染成人的病理变化的某些方面，但人们对此知之甚少 婴儿 HIV 相关 Mtb 感染的发病机制和治疗策略的功效，这些婴儿具有 免疫系统的发展会增加他们对某些传染病的脆弱性。最近的进展 对新生儿免疫的理解表明，先天反应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。儿童艾滋病毒的临床过程 研究表明，围产期获得性艾滋病毒感染发生在免疫发育的关键窗口期，并且 HIV 对这一动态过程的扰动可能是 HIV 年龄依赖性显着差异的原因 疾病进展。幼儿的结核病通常难以察觉，并且可以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 了解儿科宿主中 HIV 相关 Mtb 感染的免疫发病机制对于 提供适当的干预措施，可以降低婴儿同时感染的发病率和死亡率的风险 艾滋病毒和结核分枝杆菌。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，并已表明 新生儿免疫系统高度分化，粘膜免疫能力更强 出生时的全身系统比全身系统低，儿童 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。该提案旨在确定 SIV 感染引起的免疫学变化导致婴儿 Mtb 的严重程度增加， 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感染 免疫反应、肺部病理学、潜伏期、储存库和疾病进展。我们的目标 研究目的是： a) 描述 Mtb 对全身和粘膜发育和成熟的影响 接受或不接受免疫治疗的幼年猕猴的免疫系统； b) 比较免疫反应和 SIV/Mtb 共同感染的幼年猕猴的病理学； c) 确定是否尽早开始 ART 随后的免疫治疗可降低婴儿 HIV 相关 Mtb 感染的发病率和死亡率。由 使用全面、多管齐下的方法来确定结核分枝杆菌感染对发展的影响 和免疫系统的功能，并确定 Mtb 特异性免疫恢复的机制 SIV 感染婴儿的功能，我们的研究将增进我们对结核病免疫发病机制的理解 在艾滋病毒感染儿童中，这可能为免疫机制提供新的见解，从而可以针对 针对婴儿合并感染结核分枝杆菌的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-