Immunometabolism of M. tuberculosis/HIV co-infection
结核分枝杆菌/HIV合并感染的免疫代谢
基本信息
- 批准号:9205203
- 负责人:
- 金额:$ 19.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-13 至 2018-05-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAdultAdvanced DevelopmentAntimycobacterial AgentsBioenergeticsBiological AssayBlood CirculationCellsCellular ImmunityDataDiagnosticDiseaseEnergy MetabolismFutureGlucoseGoalsHIVHIV InfectionsHIV/TBHealthHumanImmuneImmune responseImmunityImmunologic MarkersIndividualInfectionInterventionKnowledgeLightMeasuresMetabolicMetabolic PathwayMetabolismMycobacterium bovisMycobacterium tuberculosisNatural ImmunityObservational StudyOxygen ConsumptionPathogenesisPathologyPathway interactionsPatientsPeripheralPharmaceutical PreparationsPlayPopulationPrevention approachPreventive InterventionPublic HealthPulmonary TuberculosisRegulationResearchResectedRespirationRiskRoleShapesSliceSouth AfricaStagingStructure of parenchyma of lungTechniquesTechnologyTestingTherapeuticTherapeutic InterventionTimeTuberculosisVaccinesViralWorkadaptive immunityage groupbaseclinically relevantco-infectioncohortextracellularhealthy volunteerhuman diseaseimmune functionindexinginnovationinnovative technologiesmacrophagemonocytenew technologynovelnovel diagnosticspandemic diseaseprognosticprophylacticprospectiverespiratorystable isotopetargeted treatmenttooltuberculosis treatmentvaccination against tuberculosis
项目摘要
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.
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.牛卡介苗不足以保护所有年龄段的人免受最常见的结核病感染
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ADRIE JC STEYN其他文献
ADRIE JC STEYN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ADRIE JC STEYN', 18)}}的其他基金
METABOLIC REPROGRAMMING OF T CELL ENERGY METABOLISM IN TUBERCULOSIS AND HIV
结核病和艾滋病毒中 T 细胞能量代谢的代谢重编程
- 批准号:
10373022 - 财政年份:2018
- 资助金额:
$ 19.38万 - 项目类别:
METABOLIC REPROGRAMMING OF T CELL ENERGY METABOLISM IN TUBERCULOSIS AND HIV
结核病和艾滋病毒中 T 细胞能量代谢的代谢重编程
- 批准号:
10092517 - 财政年份:2018
- 资助金额:
$ 19.38万 - 项目类别:
Interplay between the Mtb electron transport chain and carbon metabolism
Mtb 电子传递链与碳代谢之间的相互作用
- 批准号:
10512057 - 财政年份:2018
- 资助金额:
$ 19.38万 - 项目类别:
Interplay between the Mtb electron transport chain and carbon metabolism
Mtb 电子传递链与碳代谢之间的相互作用
- 批准号:
10053296 - 财政年份:2018
- 资助金额:
$ 19.38万 - 项目类别:
Interplay between the Mtb electron transport chain and carbon metabolism
Mtb 电子传递链与碳代谢之间的相互作用
- 批准号:
10290879 - 财政年份:2018
- 资助金额:
$ 19.38万 - 项目类别:
Immunometabolism of M. tuberculosis/HIV co-infection
结核分枝杆菌/HIV合并感染的免疫代谢
- 批准号:
9294970 - 财政年份:2016
- 资助金额:
$ 19.38万 - 项目类别:
Heme oxygenase-1 and the bioenergetic threshold of latent TB and HIV co-infection
血红素加氧酶-1 与潜伏性结核病和艾滋病毒双重感染的生物能阈值
- 批准号:
8898463 - 财政年份:2015
- 资助金额:
$ 19.38万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 19.38万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 19.38万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 19.38万 - 项目类别:
Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 19.38万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 19.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 19.38万 - 项目类别:
Discovery Early Career Researcher Award
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
- 批准号:
10065645 - 财政年份:2023
- 资助金额:
$ 19.38万 - 项目类别:
Collaborative R&D
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 19.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 19.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 19.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)