Immunometabolism of M. tuberculosis/HIV co-infection

全世界有近17亿人无症状地感染结核分枝杆菌（Mtb）， 结核病的病原体。此外，合并感染艾滋病毒大大增加了发展为活跃的风险。 结核病是全球公共卫生控制措施的主要障碍。唯一可用的 vaccine，M.牛卡介苗，是不足以保护所有年龄组对最常见的介绍， 肺结核虽然人们广泛认为细胞代谢在代谢中起着重要作用， 协调保护性（和破坏性）免疫反应，我们知识的一个重大空白是结核病如何 使宿主免疫代谢失调以建立持续感染。我们的长期目标是更好地 了解艾滋病毒调节结核潜伏期的机制，以及这些机制如何能够 用于治疗和预防目的。这项工作的目标是产生一个机械的 了解免疫代谢在结核分枝杆菌和艾滋病毒感染中的作用。我们的核心假设是 Mtb/HIV合并感染期间的代谢重编程驱动了失调的免疫反应， 易感宿主的致命病理这一假设是根据我们的强有力的 来自使用新鲜切除的新稳定同位素（C13-葡萄糖）掺入测定的初步数据 人结核性肺组织（“瓦尔堡切片”），其显示Mtb引起宿主细胞能量的转移 新陈代谢.其次，我们将应用新技术，如实时代谢通量分析，以非 有创测定耗氧率、细胞外酸化率、备用呼吸量， 最大呼吸和感染Mtb和/或HIV的细胞的ATP周转。这项强大的技术 还被应用于研究细菌/病毒宿主相互作用的生物能量学。第三，这项技术 使我们能够证明，从结核病患者的PBMC中分离的单核细胞的生物能量能力， 与健康志愿者相比，严重受损。理由是，成功完成这项工作， 建议将（i）建立一个新的、临床相关的结核病/艾滋病毒疾病范例， 发病过程中宿主免疫反应失调。这将推动新诊断技术的发展。 工具和宿主导向疗法，目标是受感染个体的代谢。第二，（二）该建议将 提供了一个独特的诊断/预后平台，以比较成熟的疫苗株与致病性 结核分枝杆菌，这也可能提供新的参数，以测试未来的疫苗株，并预测候选人， 在Mtb攻击后的强保护性免疫应答。这项研究是创新的，因为它 代表了一个新的和实质性的脱离现状，通过应用新的技术和独特的 患者队列检查免疫代谢作为范例，以更好地了解结核病/艾滋病毒疾病。这 这一贡献意义重大，因为它是结核病/艾滋病研究连续体的第一步， 对现有的艾滋病/结核病研究范式进行持久的、积极的改变。

Close to 1.7 billion people worldwide are asymptomatically infected with Mycobacterium tuberculosis (Mtb), the etiological agent of TB. Furthermore, co-infection with HIV dramatically increases the risk of developing active TB, and constitutes a major impediment to worldwide public health control measures. The only available vaccine, M. bovis BCG, is insufficient at protecting all age groups against the most common presentation of the disease, pulmonary TB. While it is widely recognized that cellular metabolism plays a fundamental role in orchestrating protective (and destructive) immune responses, a significant gap in our knowledge is how Mtb dysregulates host immunometabolism to establish a persistent infection. Our long-term goal is to better understand the mechanisms by which HIV modulates TB latency and how these mechanisms can be manipulated for therapeutic and prophylactic purposes. The objective of this work is to generate a mechanistic understanding of the role of immunometabolism in Mtb and HIV infection. Our central hypothesis is that metabolic reprogramming during Mtb/HIV coinfection drives a dysregulated immune response that promotes lethal pathology in susceptible hosts. This hypothesis has been formulated on the basis of our strong preliminary data derived from novel stable isotope (C13-glucose) incorporation assays using freshly resected human tuberculous lung tissue (“Warburg slices”), which show that Mtb causes a shift in host cell energy metabolism. Secondly, we will apply novel techniques such as real-time metabolic flux analysis to non- invasively measure the oxygen consumption rate, extracellular acidification rate, spare respiratory capacity, maximal respiration, and ATP turnover of cells infected with Mtb and/or HIV. This powerful technology has not yet been applied to study the bioenergetics of bacterial/viral host interaction. Thirdly, this technology has enabled us to demonstrate that the bioenergetic capacity of monocytes isolated from PBMCs in TB patients is dramatically impaired compared to that of healthy volunteers. The rationale is that successful completion of this proposal will (i) establish a new, clinically relevant paradigm of TB/HIV disease that sheds light on dysregulated host immune responses during pathogenesis. This will advance development of new diagnostic tools and host-directed therapies that target metabolism in infected individuals. Secondly, (ii) this proposal will provide a unique diagnostic/prognostic platform to compare a well-established vaccine strain with pathogenic Mtb, which may also provide new parameters to test future vaccine strains and predict candidates that will elicit robust protective immune responses upon Mtb challenge. The research is innovative, in our opinion, because it represents a new and substantive departure from the status quo by applying novel technologies and unique patient cohorts to examine immunometabolism as paradigm to better understand TB/HIV disease. This contribution is significant because it is the first step in the continuum of TB/HIV research that has the potential to make a lasting, positive change to existing paradigms in HIV/TB research.