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（由适用提供）：在宿主细胞的细胞质中识别外源DNA对于开始对DNA病毒的免疫回应至关重要。识别病毒DNA会激活许多信号通路，包括诱导潜在的抗病毒细胞因子（例如I型干扰素）。尽管胞质DNA传感途径进化为检测病毒，但我们最近的初步数据也表明，DNA依赖性刺激的激活对于对肿瘤的反应也可能至关重要。在这里，我们建议研究胞质DNA的识别如何导致自然杀伤（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细胞对病毒和肿瘤的先天识别的常见机制。我们描述了三个目标，这些目标将阐明CGAS刺激途径如何启动抗病毒和抗肿瘤反应。这些目的代表了Raulet Lab之间的紧密合作，该实验室在NK细胞和NKG2D激活受体中具有专业知识，以及顾问Russell Vance的实验室，该实验室在胞质DNA敏感性和Sting途径方面具有专业知识。目的如下：（1）确定CGAS刺途径如何在体内激活NK细胞和其他免疫细胞。我们的初步数据表明，HSV-1或合成2'3'-cgamp的刺痛接合会在体内激活NK细胞和其他免疫细胞。刺激激活导致I型IFN，STAT6依赖性趋化因子和NKG2D配体的激活产生。将这些途径与NK激活联系起来的机制以及所涉及的细胞类型的机制将在体内使用各种敲除小鼠确定。（2）确定对肿瘤的先天免疫控制是否需要CGAS插曲信号。带有e -myc转化的小鼠将跨过B细胞淋巴瘤，将交叉与CGAS刺信信号通路缺乏的小鼠交叉。我们将确定在该模型中，CGAS刺的损失是否会加速肿瘤发生。我们假设肿瘤细胞和激活NK细胞受体的配体可能的APC表达需要CGAS刺信信号传导（例如NKG2D和DNAM1）。（3）确定DNA损伤导致声学DNA的机制。我们的初步数据表明，经历了DNA损伤或经历转化的细胞会增加和异常的声学DNA，这些细胞主要来自内源性逆转录病毒/元素。在此目的中，我们将评估胞质DNA增加是否是由于逆转录病毒/元素RNA的表达增加和/或胞质逆转录酶活性增加以及/或胞质DNA外核酸外核酸外核酸酶的活性降低（例如TREX1）。