Immune control mechanisms of TB latency in the setting of HIV co-infection
HIV合并感染情况下结核潜伏期的免疫控制机制
基本信息
- 批准号:9229528
- 负责人:
- 金额:$ 44.25万
- 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:2016-04-01 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:A549Adjuvant TherapyAlveolarAlveolar MacrophagesAntiparasitic AgentsAntitubercular AgentsAntiviral AgentsAutophagocytosisCD4 Positive T LymphocytesCRISPR/Cas technologyCellsComplexCyclic AMP-Dependent Protein KinasesCyclic GMPCytoplasmic GranulesDNADataDetectionDiarrheaDiseaseDisease ProgressionDrug InteractionsDrug resistanceDrug toxicityEpithelial CellsFDA approvedFamily memberFoundationsGene ExpressionGenesGenetic TranscriptionGoalsGrowthHIVHIV InfectionsHIV-1HumanIFITM1 geneImmuneImmunologicsIndividualInfectionInflammatoryIntegral Membrane ProteinIntegration Host FactorsInterferon Type IInterferonsLaboratoriesLeadLungMediatingMessenger RNAMolecularMycobacterium tuberculosisMyeloid CellsPathway interactionsPatientsPhagosomesPharmaceutical PreparationsPhosphoric Monoester HydrolasesPhosphorylationProductionProtein FamilyProtein KinaseProtein Kinase InteractionRNA helicase ARecruitment ActivityRegimenRegulationReportingRiskRoleSTAT3 geneSignal TransductionStat3 proteinStressSyndromeTLR2 geneTestingToll-like receptorsTranscriptional ActivationTretinoinTuberculosisVirulentWorkantimicrobial drugbasebiological adaptation to stressco-infectioncytokinedesigneIF-2 Kinaseexperimental studyimmunoregulationimprovedknock-downmacrophagemembermolecular targeted therapiesmonocytemortalitymycobacterialnitazoxanidenoveloverexpressionpathogenprotein activationpublic health relevancereactivation from latencyreconstitutionresponsesensorsmall hairpin RNAsmall moleculetherapeutic targettreatment durationtuberculosis treatmentvacuolar H+-ATPaseviral RNA
项目摘要
DESCRIPTION (provided by applicant)
Mycobacterium tuberculosis (MTb) drives enhanced human immunodeficiency virus (HIV) replication and disease progression, while HIV-induced CD4+ T cell depletion dramatically increases MTb reactivation from latency and the risk of de novo MTb infection. Improved understanding of the immunological and cellular mechanisms involved in host control of latent and active TB in the context of HIV infection is critical for the design of novel treatments for TB/HIV co-infection. Here, we present preliminary data demonstrating that transcription of the antiviral interferon-induced transmembrane (IFITM) family of proteins (IFITM1, 2, and 3) is strongly induced by MTb infection of human monocytes and monocyte-derived-macrophages (MDM). Further, using shRNA, we show that IFITM1-3 restrict both MTb and HIV-1 infection in human monocytic cells. In addition, IFITM3 co-localizes with MTb in early and late endosomal compartments post-infection, and overexpression of IFITM3 results in enhanced acidification of endosomal compartments in MTb-infected monocytes. We also show that dead(d)Cas9-KRAB-mediated knock-down of the innate immune viral RNA sensors, interferon-induced, double-stranded RNA-activated protein kinase (PKR), and retinoic acid-inducible gene 1 (RIG-I), leads to greater MTb growth in human monocytic cells. Our studies of the FDA-approved small molecule drug, nitazoxanide (NTZ) widely used in parasitic diarrhea, which has previously been shown to activate PKR, induces the formation of stress granules and activates transcription of the stress response and antiviral phosphatase GADD34 in human alveolar epithelial cells, which is also induced by MTb. Furthermore, NTZ inhibits MTb and HIV infection in MDM, and suppresses TLR-mediated activation of a quiescent proviral HIV minigenome in monocytic cells. Based on these preliminary data, in this proposal we will test the following major hypotheses: (i) IFITM3 is the primary IFITM family member involved in MTb restriction in myeloid cells, and limits MTb survival and growth by promoting recruitment of v-ATPase to the mycobacterial phagosome resulting in subsequent phagosome acidification; ii) PKR and RIG-I expression and activation augment the host cell response to virulent MTb that is initiated by signals triggered by
MTb DNA early after infection; iii) PKR is required for NTZ-induced stress granule formation and activation of both GADD34 transcription itself and GADD34-mediated RIG-I activation, which leads to enhanced detection and control of both MTb and HIV; and, iv) NTZ inhibits the growth of both pathogens by disrupting basal STAT3-PKR interactions and promoting PKR-dependent autophagy. We expect to identify novel host cell mechanisms that restrict TB/HIV, including factors that are critical for MTb survival after infection of macrophages, which we anticipate will
be attractive therapeutic targets for simultaneous modulation of active/latent TB and HIV in the context of co-infection. We also anticipate that we will identify molecular and immunological correlates of NTZ-mediated anti-TB/HIV activity providing a scientific foundation for rapid repurposing of NTZ for TB/HIV.
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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ANNE GOLDFELD其他文献
ANNE GOLDFELD的其他文献
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{{ truncateString('ANNE GOLDFELD', 18)}}的其他基金
Discovery of novel regulatory territories in the TNF/LT locus
TNF/LT 基因座中新调控区域的发现
- 批准号:
10650771 - 财政年份:2022
- 资助金额:
$ 44.25万 - 项目类别:
Discovery of novel regulatory territories in the TNF/LT locus
TNF/LT 基因座中新调控区域的发现
- 批准号:
10408494 - 财政年份:2022
- 资助金额:
$ 44.25万 - 项目类别:
Immunity to TB in highly immunosuppressed HIV-infected and uninfected individuals
高度免疫抑制的艾滋病毒感染者和未感染者对结核病的免疫力
- 批准号:
9303303 - 财政年份:2016
- 资助金额:
$ 44.25万 - 项目类别:
Immunity to TB in highly immunosuppressed HIV-infected and uninfected individuals
高度免疫抑制的艾滋病毒感染者和未感染者对结核病的免疫力
- 批准号:
9205082 - 财政年份:2016
- 资助金额:
$ 44.25万 - 项目类别:
Immune control mechanisms of TB latency in the setting of HIV co-infection
HIV合并感染情况下结核潜伏期的免疫控制机制
- 批准号:
9115843 - 财政年份:2016
- 资助金额:
$ 44.25万 - 项目类别:
Host factors, inflammation, and HIV associated TB
宿主因素、炎症和 HIV 相关结核病
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9114703 - 财政年份:2015
- 资助金额:
$ 44.25万 - 项目类别:
Immune control mechanisms of TB latency in the setting of HIV co-infection
HIV合并感染情况下结核潜伏期的免疫控制机制
- 批准号:
9028020 - 财政年份:2015
- 资助金额:
$ 44.25万 - 项目类别:
T CELL SUBSETS AND THEIR FUNCTION IN TB/HIV PARADOXICAL REACTIONS
T 细胞亚群及其在 TB/HIV 矛盾反应中的功能
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7753855 - 财政年份:2009
- 资助金额:
$ 44.25万 - 项目类别:
T CELL SUBSETS AND THEIR FUNCTION IN TB/HIV PARADOXICAL REACTIONS
T 细胞亚群及其在 TB/HIV 矛盾反应中的功能
- 批准号:
7554709 - 财政年份:2009
- 资助金额:
$ 44.25万 - 项目类别:
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