Dissecting the pathogenesis of HIV-TB Immune reconstitution inflammatory syndrome
剖析 HIV-TB 免疫重建炎症综合征的发病机制
基本信息
- 批准号:10451735
- 负责人:
- 金额:$ 76.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-17 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdverse effectsAftercareAnimal ModelAnimalsAnti-Retroviral AgentsAntitubercular AgentsAutopsyBacteriaBiological MarkersBloodCD4 Lymphocyte CountCellsCessation of lifeCharacteristicsClinicalCollaborationsComplexCountryDataDevelopmentDiseaseDisease modelEarly treatmentEventGoalsGranulomaHIVHIV InfectionsHIV/TBHealthcareHeterogeneityHospitalizationHumanImageImmuneImmune responseImmune systemImmunologicsImmunologyImprove AccessIncidenceInfectionInflammationInflammatoryKnowledgeLeadMeasuresMedical ResearchMicrobiologyMissionModalityModelingMorbidity - disease rateMycobacterium tuberculosisNational Institute of Allergy and Infectious DiseaseNaturePathogenesisPathologyPatientsPersonsPharmaceutical PreparationsPharmacotherapyPlasmaPositron-Emission TomographyPrednisonePreventionPrevention strategyProcessResearch InfrastructureResearch PersonnelResourcesRiskSIVSigns and SymptomsSiteSymptomsSyndromeTechnologyTherapeuticTimeTissuesTuberculosisUnited States National Institutes of HealthVaccinesVirusadaptive immune responseantiretroviral therapyclinical predictorsco-infectionglobal healthhigh riskhuman diseasehuman modelimmune functionimmune reconstitutionimprovedin vivo imaginginsightlymph nodesmolecular imagingmortalitymortality risknew technologynonhuman primatepathogenpreventprogramspulmonary granulomaradiological imagingresponsetime intervaltooltuberculosis drugstuberculosis treatmentvirtual
项目摘要
Despite major advances in global health care, there were an estimated 1.5 millions deaths and 10 million new
cases of tuberculosis (TB) in 2018. Nearly 1 million people living with HIV developed tuberculosis (TB). Co-
infection with HIV and TB is associated with high morbidity and mortality and treatment with TB drugs and anti-
retroviral (ART) therapy is now universally available. TB drug treatment followed by ART improves long term
survival, particularly among those whose immune systems are severely suppressed from HIV infection. Signs
and symptoms of disease improve soon after treatment is started but, in many cases, disease can recur and
appear clinically worse as the immune system is being re-established from ART. This is known as TB-
associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and is more common among patients
with severely suppressed immune systems before treatment and those who have a short time interval between
starting TB treatment and ART. Very little is known about how or why TB-IRIS occurs and how to best to treat
or even prevent it. We hypothesize that symptoms of TB-IRIS are driven by the dynamic interaction between
the immune system, Mycobacterium tuberculosis (Mtb, the bacteria that causes TB) and HIV deep within
infected tissues in the body such as the lung granuloma. Virtually nothing is known about what happens in the
tissues where both Mtb and HIV interact during TB-IRIS. This proposal will develop an animal model of TB-
IRIS by taking advantage of our pre-existing model of HIV-TB co-infection in which animals with SIV-Mtb co-
infection undergo TB drug treatment and ART just like humans. We will use sophisticated imaging,
immunology and microbiologic tools to better understand how and why TB-IRIS develops and what factors can
predict its emergence. Aim 1 will determine how often TB-IRIS occurs in this model and to what extent Mtb and
SIV remain in the tissues during treatment. We will also perform a detailed examination of the changes that
occur in the tissues but especially the lungs (granulomas) and lymph nodes through serial in vivo images to
better understand the events that lead to TB-IRIS and its predictors. In Aim 2, we will perform a detailed
examination of the immunologic events in the tissues and blood during TB-IRIS. Tissue specific (lung
granulomas and lymph nodes) immune responses will be correlated with the amount of Mtb bacteria and virus
with the imaging findings so that we can better understand the causes of TB-IRIS. Our short term goal is to
better understand the pathogenesis of TB-IRIS in this proposal and these findings will ultimately lead to better
treatment and prevention of TB-IRIS which is our long term goal.
尽管全球卫生保健取得了重大进展,但估计仍有150万人死亡,
2018年结核病(TB)近100万艾滋病毒感染者患上了结核病。共
感染艾滋病毒和结核病与高发病率和死亡率以及结核病药物和抗结核药物治疗有关,
逆转录病毒疗法现已普遍提供。抗逆转录病毒疗法后的结核病药物治疗可长期改善
艾滋病毒感染者的免疫系统受到严重抑制。迹象
并且疾病症状在治疗开始后很快改善,但是在许多情况下,疾病可以复发,
随着免疫系统从抗逆转录病毒治疗中重新建立,临床表现更差。这被称为结核病-
相关的免疫重建炎症综合征(TB-IRIS),在患者中更常见
在治疗前免疫系统受到严重抑制的人,以及那些在治疗前
开始TB治疗和ART。关于TB-IRIS如何或为什么发生以及如何最好地治疗
我们假设TB-IRIS的症状是由以下因素之间的动态相互作用驱动的:
免疫系统,结核分枝杆菌(Mtb,导致结核病的细菌)和艾滋病毒深入内部
体内受感染的组织,如肺肉芽肿。事实上,我们对在地球上发生的事情一无所知。
结核分枝杆菌和艾滋病毒在TB-IRIS期间相互作用的组织。该提案将开发结核病的动物模型-
IRIS通过利用我们预先存在的HIV-TB共感染模型,
感染者像人类一样接受结核病药物治疗和抗逆转录病毒疗法。我们将使用先进的成像技术,
免疫学和微生物学工具,以更好地了解如何和为什么TB-IRIS发展,以及哪些因素可以
预测它的出现。目标1将确定在该模型中TB-IRIS发生的频率以及Mtb和
SIV在治疗过程中仍然存在于组织中。我们还将详细检查
发生在组织中,但特别是肺(肉芽肿)和淋巴结,通过一系列体内图像,
更好地了解导致TB-IRIS的事件及其预测因素。在目标2中,我们将执行详细的
检测TB-IRIS期间组织和血液中的免疫学事件。组织特异性(肺
肉芽肿和淋巴结)的免疫应答将与Mtb细菌和病毒的量相关
结合影像学检查结果,以便更好地了解TB-IRIS的病因。我们的短期目标是
更好地了解TB-IRIS的发病机制,这些发现将最终导致更好的
治疗和预防TB-IRIS是我们的长期目标。
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)
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JoAnne L. Flynn其他文献
This information is current as Infection Mycobacterium tuberculosis during Antimicrobial Responses with Caseation Mediated − Early Host Immunity Control of Lesion Sterilization by Balancing Computational Modeling Predicts IL-10
此信息是当前的感染结核分枝杆菌在干酪介导的抗菌反应期间通过平衡计算模型预测 IL-10 进行病灶灭菌的早期宿主免疫控制
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:0
- 作者:
Nicholas A. Cilfone;Christopher B Ford;Simeone Marino;Joshua T Mattila;H. Gideon;JoAnne L. Flynn;Denise E. Kirschner;J. Linderman - 通讯作者:
J. Linderman
Modeling pathogen and host: <em>in vitro</em>, <em>in vivo</em> and <em>in silico</em> models of latent <em>Mycobacterium tuberculosis</em> infection
- DOI:
10.1016/j.ddmod.2005.05.019 - 发表时间:
2005-06-01 - 期刊:
- 影响因子:
- 作者:
P. Ling Lin;Denise Kirschner;JoAnne L. Flynn - 通讯作者:
JoAnne L. Flynn
emIn silico/em identification and synthesis of a multi-drug loaded MOF for treating tuberculosis
- DOI:
10.1016/j.jconrel.2022.10.024 - 发表时间:
2022-12-01 - 期刊:
- 影响因子:11.500
- 作者:
Abhinav P. Acharya;Kutay B. Sezginel;Hannah P. Gideon;Ashlee C. Greene;Harrison D. Lawson;Sahil Inamdar;Ying Tang;Amy J. Fraser;Kush V. Patel;Chong Liu;Nathaniel L. Rosi;Stephen Y. Chan;JoAnne L. Flynn;Christopher E. Wilmer;Steven R. Little - 通讯作者:
Steven R. Little
This information is current as Infection in BALB / c Mice tuberculosis Mycobacterium the Control of Chronic The Chemokine Receptor CXCR 3 Attenuates
此信息当前为 BALB / c 小鼠结核分枝杆菌感染控制慢性趋化因子受体 CXCR 3 减弱
- DOI:
- 发表时间:
2007 - 期刊:
- 影响因子:0
- 作者:
S. Chakravarty;Jiayong Xu;Bao Lu;Craig Gerard;JoAnne L. Flynn;John Chan - 通讯作者:
John Chan
SARS-CoV-2 Receptor ACE2 is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Enriched in Specific Cell Subsets Across Tissues
SARS-CoV-2 受体 ACE2 是人气道上皮细胞中的干扰素刺激基因,富含组织中的特定细胞亚群
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
Carly N Ziegler;Samuel J. Allon;Sarah K Nyquist;Ian M. Mbano;Vincent N Miao;Yuming Cao;Ashraf S. Yousif;Julia Bals;B. Hauser;J. Feldman;Christoph Muus;Marc H Wadsworth Ii;S. Kazer;T. Hughes;B. Doran;G. J. Gatter;Marko Vukovic;C. Tzouanas;F. Taliaferro;Zhiru Guo;Jennifer P. Wang;Daniel F Dwyer;K. Buchheit;Joshua A. Boyce;Nora A. Barrett;T. Laidlaw;Shaina L. Carroll;Lucrezia Colonna;V. Tkachev;Alison Yu;Henqi Betty Zheng;H. Gideon;Caylin G. Winchell;P. Lin;Bonnie Berger;A. Leslie;JoAnne L. Flynn;Sarah M Fortune;R. Finberg;Leslie S. Kean;Manuel Garber;Aaron Schmidt;D. Lingwood;A. Shalek;J. Ordovas;Hca Lung Biological Network - 通讯作者:
Hca Lung Biological Network
JoAnne L. Flynn的其他文献
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{{ truncateString('JoAnne L. Flynn', 18)}}的其他基金
Enhancing cytotoxic lymphocytes in a TB vaccine strategy
在结核病疫苗策略中增强细胞毒性淋巴细胞
- 批准号:
10462928 - 财政年份:2022
- 资助金额:
$ 76.37万 - 项目类别:
Enhancing cytotoxic lymphocytes in a TB vaccine strategy
在结核病疫苗策略中增强细胞毒性淋巴细胞
- 批准号:
10580073 - 财政年份:2022
- 资助金额:
$ 76.37万 - 项目类别:
Dissecting the pathogenesis of HIV-TB Immune reconstitution inflammatory syndrome
剖析 HIV-TB 免疫重建炎症综合征的发病机制
- 批准号:
10097199 - 财政年份:2020
- 资助金额:
$ 76.37万 - 项目类别:
Dissecting the pathogenesis of HIV-TB Immune reconstitution inflammatory syndrome
剖析 HIV-TB 免疫重建炎症综合征的发病机制
- 批准号:
10667439 - 财政年份:2020
- 资助金额:
$ 76.37万 - 项目类别:
Dissecting the pathogenesis of HIV-TB Immune reconstitution inflammatory syndrome
剖析 HIV-TB 免疫重建炎症综合征的发病机制
- 批准号:
10240712 - 财政年份:2020
- 资助金额:
$ 76.37万 - 项目类别:
Predicting protective T-cell responses in Tuberculosis using a systems biology approach
使用系统生物学方法预测结核病中的保护性 T 细胞反应
- 批准号:
9072491 - 财政年份:2016
- 资助金额:
$ 76.37万 - 项目类别:
The Effects of M. tuberculosisInfection on Lung Microbiome in Macaques
结核分枝杆菌感染对猕猴肺部微生物组的影响
- 批准号:
9018134 - 财政年份:2016
- 资助金额:
$ 76.37万 - 项目类别:
An adjuvant that promotes TH1/TH17 and CD8 T cells in a tuberculosis vaccine
一种在结核疫苗中促进 TH1/TH17 和 CD8 T 细胞的佐剂
- 批准号:
8607041 - 财政年份:2013
- 资助金额:
$ 76.37万 - 项目类别:
An adjuvant that promotes TH1/TH17 and CD8 T cells in a tuberculosis vaccine
一种在结核疫苗中促进 TH1/TH17 和 CD8 T 细胞的佐剂
- 批准号:
8994259 - 财政年份:2013
- 资助金额:
$ 76.37万 - 项目类别:
An adjuvant that promotes TH1/TH17 and CD8 T cells in a tuberculosis vaccine
一种在结核疫苗中促进 TH1/TH17 和 CD8 T 细胞的佐剂
- 批准号:
9208083 - 财政年份:2013
- 资助金额:
$ 76.37万 - 项目类别:
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