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

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.
 描述(由申请人提供) 结核分枝杆菌(MTB)促进了人类免疫缺陷病毒(HIV)的复制和疾病进展,而HIV导致的CD4+T细胞枯竭显著增加了MTB从潜伏期重新激活和从头感染MTB的风险。在艾滋病毒感染的背景下,更好地了解宿主控制潜伏期和活动性结核病所涉及的免疫学和细胞机制,对于设计结核病/艾滋病毒混合感染的新疗法至关重要。在这里,我们提供了初步的数据表明,抗病毒干扰素诱导的跨膜蛋白(IFITM)家族(IFITM1、2和3)的转录受到MTB感染人类单核细胞和单核细胞来源的巨噬细胞(MDM)的强烈诱导。此外,利用shRNA,我们证明了IFITM1-3同时限制了MTB和HIV-1在人单核细胞中的感染。此外,IFITM3与MTB共定位于感染后早期和晚期的内体隔室,IFITM3的过度表达导致感染MTB的单核细胞内体隔间的酸化增强。我们还发现,DEAD(D)Cas9-KRAb介导的先天免疫病毒RNA传感器、干扰素诱导的双链RNA激活蛋白激酶(PKR)和维甲酸诱导基因1(RIG-I)的下调,导致人单核细胞中MTB的更大增长。我们对FDA批准的治疗寄生性腹泻的小分子药物Nitazoxanide(NTZ)的研究表明,它可以激活PKR,诱导应激颗粒的形成,并激活人肺泡上皮细胞应激反应和抗病毒磷酸酶Gadd34的转录,这也是MTB诱导的。此外,NTZ抑制MDM中的MTB和HIV感染,并抑制TLR介导的单核细胞中静止的前HIV微型基因组的激活。基于这些初步数据,在这项提案中,我们将检验以下主要假设:(I)IFITM3是参与限制髓系细胞中MTB的主要IFITM家族成员,通过促进v-ATPase向分枝杆菌吞噬小体的募集而限制MTB的生存和生长,从而导致随后的吞噬小体酸化;ii)PKR和RIG-I的表达和激活增强了宿主细胞对强毒MTB的反应,该反应是由 MTB DNA在感染后早期;iii)PKR是NTZ诱导的应激颗粒形成和Gadd34转录本身激活以及Gadd34介导的RIG-I激活所必需的,这导致对MTB和HIV的增强检测和控制;以及iv)NTZ通过破坏基本的STAT3-PKR相互作用和促进依赖PKR的自噬来抑制这两种病原体的生长。我们希望识别限制结核/艾滋病毒的新宿主细胞机制,包括感染巨噬细胞后对结核杆菌存活至关重要的因素,我们预计巨噬细胞将 在合并感染的情况下,成为同时调节活动性/潜伏性结核病和艾滋病毒的有吸引力的治疗目标。我们还预计,我们将确定NTZ介导的抗结核病/HIV活性的分子和免疫学相关性,为NTZ快速重新用于结核病/HIV提供科学基础。

项目成果

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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:
Innate Immune Control of TB and HIV
结核病和艾滋病毒的先天免疫控制
  • 批准号:
    10426882
  • 财政年份:
    2021
  • 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
  • 批准号:
    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
  • 批准号:
    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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