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)驱动增强的人类免疫缺陷病毒(HIV)复制和疾病进展,而HIV诱导的CD 4 + T细胞耗竭显著增加MTb从潜伏期的再活化和新发MTb感染的风险。在HIV感染的背景下,对宿主控制潜伏性和活动性TB所涉及的免疫和细胞机制的进一步理解对于设计TB/HIV合并感染的新型治疗方法至关重要。在这里,我们提出的初步数据表明,转录的抗病毒干扰素诱导的跨膜(IFITM)家族的蛋白质(IFITM 1,2和3)是强烈诱导MTb感染的人单核细胞和单核细胞衍生的巨噬细胞(MDM)。此外,使用shRNA,我们表明IFITM 1 -3限制MTb和HIV-1在人单核细胞中的感染。此外,IFITM 3与MTb共定位于感染后的早期和晚期内体区室中,并且IFITM 3的过表达导致MTb感染的单核细胞内体区室的酸化增强。我们还表明,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)和视黄酸诱导基因1(RIG-I)的死亡(d)敲除,导致MTb更大的生长在人类单核细胞中。我们的研究FDA批准的小分子药物,硝唑尼特(NTZ)广泛用于寄生虫性腹泻,以前已被证明激活PKR,诱导应激颗粒的形成,并激活应激反应和抗病毒磷酸酶GADD 34在人肺泡上皮细胞,这也是由MTb诱导的转录。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前病毒HIV微型基因组的激活。(i)IFITM 3是参与骨髓细胞中MTb限制的主要IFITM家族成员,并通过促进v-ATP酶向分枝杆菌吞噬体的募集导致随后的吞噬体酸化来限制MTb存活和生长; ii)PKR和RIG-I的表达和活化增强了宿主细胞对毒性MTb的应答,所述应答由以下物质触发的信号引发: 感染后早期MTb DNA; iii)PKR是NTZ诱导的应激颗粒形成和GADD 34转录本身的激活以及GADD 34介导的RIG-I激活所需的,这导致MTb和HIV的检测和控制增强;以及iv)NTZ通过破坏基础STAT 3-PKR相互作用并促进PKR依赖性自噬来抑制两种病原体的生长。我们希望确定限制TB/HIV的新宿主细胞机制,包括对巨噬细胞感染后MTb存活至关重要的因素,我们预计这将 是在合并感染的情况下同时调节活动性/潜伏性TB和HIV的有吸引力的治疗靶标。我们还预计,我们将确定NTZ介导的抗TB/HIV活性的分子和免疫学相关性,为快速重新利用NTZ治疗TB/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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