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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：
9115843
负责人：
ANNE GOLDFELD
金额：
$ 44.25万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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：
https://reporter.nih.gov/project-details/9115843
关键词：
A549 ATP phosphohydrolase Adjuvant Therapy Alveolar Alveolar Macrophages Antiparasitic Agents Antitubercular Agents Antiviral Agents Autophagocytosis CD4 Positive T Lymphocytes CRISPR/Cas technology Cells Complex Cyclic GMP Cytoplasmic Granules DNA Data Detection Diarrhea Disease Disease Progression Drug Interactions Drug resistance Drug toxicity Epithelial Cells FDA approved Family member Foundations Gene Expression Genes Genetic Transcription Goals Growth HIV HIV-1 Human IFITM1 gene Immune Individual Infection Inflammatory Integration Host Factors Interferon Type I Interferons Laboratories Lead Lung Mediating Membrane Messenger RNA Molecular Mycobacterium tuberculosis Myeloid Cells Pathway interactions Patients Phagosomes Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Production Protein Family RNA helicase A Regimen Regulation Reporting Risk Role STAT3 gene Signal Transduction Stress Syndrome T-Cell Depletion TLR2 gene Testing Toll-like receptors Transcriptional Activation Tretinoin Tuberculosis Virulent Virus Diseases Virus Replication Work antimicrobial drug base biological adaptation to stress co-infection cytokine design eIF-2 Kinase improved knock-down macrophage member molecular targeted therapies monocyte mortality mycobacterial nitazoxanide novel overexpression pathogen public health relevance reactivation from latency reconstitution research study response sensor small hairpin RNA small molecule therapeutic target treatment duration tuberculosis treatment viral 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.