STING-dependent activation of Natural Killer cells by viral and tumor DNA

病毒和肿瘤 DNA 对自然杀伤细胞的 STING 依赖性激活

基本信息

批准号：
8851516
负责人：
DAVID H RAULET
金额：
$ 38.32万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851516
关键词：
Activated Natural Killer Cell Address Agonist Antiviral Agents Antiviral Response B-Cell Lymphomas Binding Cell Communication Cells Collaborations Cyclic GMP Cytosol DNA DNA Damage DNA Viruses Data Detection Development Elements Endogenous Retroviruses Exhibits Family Herpesviridae Herpesvirus 1 Immune Immune response Immunologic Surveillance Immunotherapeutic agent Injection of therapeutic agent Interferon Type I Interferons Knockout Mice Laboratories Laboratory Study Ligand Binding Ligands Link Mediator of activation protein Modeling Molecular Mus NK Cell Activation Natural Killer Cells Nucleotides Oncogenic Viruses Pathway interactions Positioning Attribute Production RNA RNA-Directed DNA Polymerase Research Personnel Retroelements Retroviridae Role STAT6 gene Second Messenger Systems Signal Pathway Signal Transduction Signaling Molecule Source TREX1 gene Testing Transgenes Vaccines Viral Virus Virus Diseases cell type chemokine cytokine exodeoxyribonuclease experience immune activation improved in vivo insight neoplastic cell phosphodiester professor public health relevance receptor response second messenger sensor tumor tumor DNA tumorigenesis viral DNA

项目摘要

DESCRIPTION (provided by applicant): Recognition of foreign DNA in the cytosol of host cells is critical for the initiation of immune responses to DNA viruses. Recognition of viral DNA activates numerous signaling pathways, including the induction of potent antiviral cytokines such as type I interferons. Although the cytosolic DNA-sensing pathway evolved to detect viruses, our recent preliminary data also suggest that DNA-dependent activation of STING may also be critical in the response to tumors. Here we propose to investigate how recognition of cytosolic DNA leads to activation of anti-tumor and anti-viral responses by Natural Killer (NK) cells. Our overall hypothesis is that cytosolic detection of DNA is a common mechanism underlying innate recognition of viruses and tumors by NK cells. We describe three Aims that will illuminate how the cGAS-STING pathway initiates anti-viral and anti-tumor responses. These Aims represent a close collaboration between the Raulet Lab, which has expertise in NK cells and the NKG2D activating receptor, and the lab of consultant Russell Vance, which has expertise in cytosolic DNA sensing and the STING pathway. The Aims are as follows: (1) Determine how the cGAS-STING pathway activates NK cells and other immune cells in vivo. Our preliminary data show that STING engagement by HSV-1 or synthetic 2'3'-cGAMP activates NK cells and other immune cells in vivo. STING activation leads to production of type I IFN, STAT6-dependent chemokines, and activation of NKG2D ligands. The mechanisms linking these pathways to NK activation, and the cell types involved, will be determined in vivo using various knockout mice. (2) Determine if cGAS-STING signaling is required for innate immune control of tumors. Mice harboring an E¿-myc transgene, which develop B cell lymphomas, will be crossed to mice deficient in the cGAS-STING signaling pathway. We will determine whether loss of cGAS-STING accelerates tumorigenesis in this model. We hypothesize that cGAS-STING signaling is required for tumor cell and possibly APC expression of ligands that activate NK cell receptors (e.g., NKG2D and DNAM1). (3) Determine the mechanisms by which DNA damage leads to accumulation of cytosolic DNA. Our preliminary data indicate that cells experiencing DNA damage or undergoing transformation exhibit increased and aberrant accumulation of cytosolic DNA derived largely from endogenous retroviruses/elements. In this Aim we will assess whether increased cytosolic DNA is due to increased expression of retrovirus/element RNA, and/or increased cytosolic reverse transcriptase activity, and/or decreased activity of cytosolic DNA exonucleases (e.g., TREX1).

描述（由申请人提供）：宿主细胞胞浆中外源DNA的识别对于启动针对DNA病毒的免疫反应至关重要。病毒DNA的识别可激活多种信号传导途径，包括诱导有效的抗病毒细胞因子，例如I型干扰素。尽管细胞质 DNA 传感途径的进化是为了检测病毒，但我们最近的初步数据还表明，DNA 依赖性的 STING 激活可能在肿瘤反应中也至关重要。在此，我们建议研究如何识别细胞质 DNA。导致自然杀伤 (NK) 细胞激活抗肿瘤和抗病毒反应。我们的总体假设是，DNA 的胞质检测是 NK 细胞先天识别病毒和肿瘤的常见机制。我们描述了三个目标。阐明 cGAS-STING 通路如何启动抗病毒和抗肿瘤反应。这些目标代表了在 NK 细胞和 NKG2D 激活受体方面拥有专业知识的 Raulet 实验室与顾问 Russell Vance 实验室在细胞质 DNA 传感和 STING 通路方面拥有专业知识，其目标如下：（1）确定 cGAS-STING 通路如何在体内激活 NK 细胞和其他免疫细胞。 HSV-1 或合成的 2'3'-cGAMP 的参与会在体内激活 NK 细胞和其他免疫细胞，从而导致 I 型 IFN、STAT6 依赖性趋化因子的产生，以及 STAT6 依赖性趋化因子的激活。 NKG2D 配体。将使用各种基因敲除小鼠体内确定这些途径与 NK 激活的机制以及所涉及的细胞类型。 (2) 确定携带 E 的小鼠的先天免疫控制是否需要 cGAS-STING 信号传导。 ¿将产生 B 细胞淋巴瘤的 -myc 转基因与 cGAS-STING 信号通路缺陷的小鼠杂交，我们将确定 cGAS-STING 的缺失是否会加速该模型中的肿瘤发生。细胞和可能的 APC 表达激活 NK 细胞受体的配体（例如 NKG2D 和 DNAM1） (3) 确定 DNA 损伤导致累积的机制。我们的初步数据表明，经历 DNA 损伤或经历转化的细胞表现出主要源自内源性逆转录病毒/元件的胞质 DNA 的增加和异常积累。在此目的中，我们将评估胞质 DNA 的增加是否是由于逆转录病毒/元件表达的增加。 RNA，和/或胞质逆转录酶活性增加，和/或胞质 DNA 核酸外切酶（例如 TREX1）活性降低。