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
• 负责人: ANNE GOLDFELD
• 金额: $ 44.13万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9028020
• 关键词: Address; Alveolar Macrophages; Anti-Retroviral Agents; Antitubercular Agents; Area; Autophagocytosis; Biological Models; CD4 Positive T Lymphocytes; Cells; Cessation of life; Data; Development; Disease; Disease Progression; Double-Stranded RNA; Drug resistance; Drug toxicity; Epithelial Cells; FDA approved; Foundations; Gene Expression; Genes; Genetic Transcription; Goals; Growth; HIV; HIV Long Terminal Repeat; HIV-1; Hepatitis C; Human; Hypersensitivity skin testing; Immune; Immune response; Immunosuppression; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Influenza; Integration Host Factors; Interferons; Laboratories; Lead; Lesion; Lipids; Lung; Lymphocyte; Lysosomes; Mediating; Membrane Proteins; Metabolic; Molecular; Mycobacterium tuberculosis; Myeloid Cells; Organism; Patients; Phagosomes; Pharmaceutical Preparations; Proteins; Protozoa; Proviruses; Regulation; Risk; Role; Signal Pathway; Signal Transduction Pathway; Source; Syndrome; T-Cell Depletion; Testing; Therapeutic; Tuberculosis; Viral; Virus Diseases; Virus Replication; base; co-infection; design; eIF-2 Kinase; improved; in vivo; isoniazid; lipid biosynthesis; macrophage; monocyte; mortality; mycobacterial; new therapeutic target; nitazoxanide; novel; pathogen; public health relevance; reactivation from latency; reconstitution; research study; small molecule; therapeutic target; transmission process; treatment strategy; tuberculosis treatment; virus pathogenesis; Address; Alveolar Macrophages; Anti-Retroviral Agents; Antitubercular Agents; Area; Autophagocytosis; Biological Models; CD4 Positive T Lymphocytes; Cells; Cessation of life; Data; Development; Disease; Disease Progression; Double-Stranded RNA; Drug resistance; Drug toxicity; Epithelial Cells; FDA approved; Foundations; Gene Expression; Genes; Genetic Transcription; Goals; Growth; HIV; HIV Long Terminal Repeat; HIV-1; Hepatitis C; Human; Hypersensitivity skin testing; Immune; Immune response; Immunosuppression; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Influenza; Integration Host Factors; Interferons; Laboratories; Lead; Lesion; Lipids; Lung; Lymphocyte; Lysosomes; Mediating; Membrane Proteins; Metabolic; Molecular; Mycobacterium tuberculosis; Myeloid Cells; Organism; Patients; Phagosomes; Pharmaceutical Preparations; Proteins; Protozoa; Proviruses; Regulation; Risk; Role; Signal Pathway; Signal Transduction Pathway; Source; Syndrome; T-Cell Depletion; Testing; Therapeutic; Tuberculosis; Viral; Virus Diseases; Virus Replication; base; co-infection; design; eIF-2 Kinase; improved; in vivo; isoniazid; lipid biosynthesis; macrophage; monocyte; mortality; mycobacterial; new therapeutic target; nitazoxanide; novel; pathogen; public health relevance; reactivation from latency; reconstitution; research study; small molecule; therapeutic target; transmission process; treatment strategy; tuberculosis treatment; virus pathogenesis

 DESCRIPTION (provided by applicant): MTb (Mycobacterium tuberculosis) drives enhanced HIV replication and disease progression and, conversely, HIV-induced CD4+ T cell depletion increases risk of de novo MTb infection and, more importantly, MTb reactivation from latency. Alveolar macrophages (AMs) are a primary target of MTb upon transmission and are also a major source of slowly replicating and/or dormant mycobacterial in granulomous lesions. AMs are also infected by HIV acutely and harbor latent HIV. MTb replication within AMs also drives local inflammation in the lung, which in can in turn drive HIV reactivation from latency. Thus, improved understanding of the immunological and cellular mechanisms involved in the control of latent and active TB in the context of HIV infection in macrophages is critical for the design of novel treatments aimed at controlling co-infection and expediting the clearance of latent organisms to reduce risk of MTb reactivation. Our preliminary studies have demonstrated that an interferon-stimulated gene (ISG) product, interferon-inducible trans-membrane protein 3 (IFITM3), is induced by MTb infection and inhibits MTb and HIV-1 infection of human monocytes and monocyte -derived-macrophages (MDM). We have also found that the FDA-approved small molecule nitazoxanide (NTZ) induces expression of IFITM3 and also induces the HIV restriction factor SAMHD1. Furthermore, we have shown that NTZ inhibits MTb and HIV infection in monocytes and MDM, and suppresses MTb- and TLR- mediated activation of a silent mini HIV-1 provirus in monocytic cells. Based on our preliminary data, we will test the major hypothesis that (i) IFITM3 is a criticl immune modulator that inhibits MTb/HIV-1 co-infection and MTb survival in target cells of the lung, and (ii) that NTZ inhibits growth of both pathogens through direct stimulation of IFITM3, as well as additional host factors including PKR and, in the case of HIV-1 specifically, SAMHD1. Specifically, in Aim 1 we will test the hypotheses that IFITM3 is a critical immune modulator of TB/HIV co-infection, and that it restricts MTb infection via perturbation of host lipid biosynthesi and localization to the maturing phagosome. In Aim 2 we will focus on elucidating the mechanisms involved in NTZ inhibition of MTb and HIV infection of myeloid cells. We will test the hypothesis that NTZ inhibits MTb via its induction of IFITM3 and PKR, and that it inhibits HIV infection via its induction/activation of SAMHD1 and PKR. Furthermore, we will investigate whether NTZ's inhibitory effect upon HIV and TB involves stimulation of PKR- dependent autophagy, leading to enhanced viral and bacterial degradation. We expect to identify novel IFITM3-associated mechanisms of dual TB/HIV suppression, including those that are critical for MTb survival and metabolic switching to dormancy that will serve as attractive targets for simultaneous modulation of both latent and active TB disease in the context of HIV co-infection. We also anticipate that we will identify molecular and immunological correlates of NTZ-mediated anti-TB/HIV activity that will provide a foundation for the rapid repurposing of NTZ as a treatment of latent TB and TB/HIV.

 描述（由申请人提供）： MTB（结核分枝杆菌）驱动了增强的HIV复制和疾病进展，相反，HIV诱导的CD4+ T细胞耗竭会增加从头MTB感染的风险，更重要的是，MTB从延迟中重新激活。肺泡巨噬细胞（AMS）是传播时MTB的主要目标，也是颗粒病变中缓慢复制和/或休眠分枝杆菌缓慢复制和/或休眠的主要来源。 AM还被HIV感染，并伴有潜在的艾滋病毒。 AMS内的MTB复制还驱动肺中的局部炎症，进而驱动潜伏期的HIV重新激活。因此，在巨噬细胞中艾滋病毒感染中控制潜在和活性结核病涉及的免疫和细胞机制的了解对设计旨在控制共同感染并加快潜在生物体的清除以减少MTB重新激活的风险是至关重要的。我们的初步研究表明，干扰素刺激的基因（ISG）产物，干扰素诱导的跨膜蛋白3（IFITM3）是由MTB感染诱导的，并抑制了人类单核细胞和单核细胞的MTB和HIV-1感染。我们还发现，FDA批准的小分子硝酸分子（NTZ）会影响IFITM3的表达，并诱导HIV限制因子SAMHD1。此外，我们已经表明，NTZ抑制了单核细胞和MDM中的MTB和HIV感染，并抑制了单核细胞中静音迷你HIV-1病毒的MTB和TLR介导的激活。根据我们的初步数据，我们将检验以下主要假设：（i）IFITM3是一种关键的免疫调节剂，抑制MTB/HIV-1共同感染​​和MTB在肺靶细胞中的存活，并且（ii）NTZ通过直接刺激IFITM3的直接刺激IFITM3的病原体生长，包括IFITM3的直接刺激，包括Sam的其他案例，以及其他案例。具体而言，在AIM 1中，我们将测试IFITM3是TB/HIV共感染的关键免疫调节剂的假设，并且它通过扰动宿主脂质生物合成和定位来限制MTB感染并将其定位到成熟的吞噬体。在AIM 2中，我们将着重于阐明与MTB抑制MTB和HIV感染有关的机制。我们将检验以下假设：NTZ通过诱导IFITM3和PKR抑制MTB，并通过其诱导/激活SAMHD1和PKR抑制HIV感染。此外，我们将研究NTZ对HIV和TB的抑制作用是否涉及刺激PKR依赖性自噬，从而导致病毒和细菌降解增强。我们期望确定双重结核/HIV抑制的新型IFITM3相关机制，包括那些对于MTB存活至关重要的机制，以及在HIV共同感染中对潜在和活性TB疾病的简单调节的有吸引力的目标。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，这将为NTZ快速重新利用作为对潜在的TB和TB/HIV的治疗提供基础。