The natural killer cell response against mouse cytomegalovirus infection

自然杀伤细胞对小鼠巨细胞病毒感染的反应

• 批准号: 8340432
• 负责人: Joseph Chai-Yuen Sun
• 金额: $ 45.67万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-18 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8340432
• 关键词: Activated Natural Killer Cell; Address; Anti-Inflammatory Agents; Anti-inflammatory; Biological; Biology; Boxing; Cancer Patient; Cell physiology; Cells; Clinical; Communicable Diseases; Complement; Cytokine Signaling; Cytomegalovirus; Cytomegalovirus Infections; Development; Disease; Effector Cell; Engineering; Exhibits; Family; Generations; Goals; Grant; Health; Homeostasis; Host Defense; Human; Immune; Immune response; Immune system; Immunization; Immunocompromised Host; Immunosuppressive Agents; Individual; Infection; Inflammation; Inflammatory; Interferons; Interleukin-12; Interleukin-18; K-Series Research Career Programs; Knockout Mice; Lead; Life; Maintenance; Mediating; Memory; Modeling; Molecular; Mouse Strains; Murid herpesvirus 1; Mus; NK Cell Activation; Natural Killer Cells; Newborn Infant; Pathogenesis; Pathway interactions; Play; Predisposition; Production; Reagent; Regulation; Resources; Role; STAT4 gene; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; System; T-bet protein; Therapeutic; Transgenic Mice; Transgenic Organisms; Transplant Recipients; Viral; Virus; Virus Diseases; arm; base; cytokine; interleukin-12 receptor; mouse model; novel; pathogen; receptor; research study; response; therapeutic target; tool; transcription factor

DESCRIPTION (provided by applicant): Natural killer (NK) cells comprise an arm of the immune system that specifically target virus-infected host cells. NK cells have recently been demonstrated in mouse and humans to possess novel features including the ability to generate immune "memory" following viral infection. NK cell-deficiency in humans results in severe health complications due to susceptibility to a variety of viral infections. Our long-term goals are to understand the general biology of NK cells and the molecular basis by which these powerful effector cells can mediate protection against pathogen invasion. Mouse cytomegalovirus (MCMV) infection is a well-characterized system for the study of anti- viral NK cell responses. The pathogenesis of MCMV and immune evasion strategies employed by this virus closely mimic features of human cytomegalovirus (HCMV), thus providing a good model for HCMV infection, which causes life-threatening disease in newborns and immunocompromised individuals. Together with the abundance of cutting- edge immunological tools and reagents available only in mice, MCMV infection presents a powerful model for identifying the molecular requirements that control activation and inhibition of NK cells responses. Using this model, our preliminary studies indicate that pro-inflammatory cytokines such as IL-12 play an important role in the generation of NK cell "memory" following MCMV infection. The overall goals of this proposal are to understand the influence of opposing pro- and anti-inflammatory cytokine signaling pathways on the response of NK cells against viral infection. Aims 1 and 2 will build upon our preliminary findings and investigate the role of pro-inflammatory and regulatory cytokines, and downstream signaling components, on the generation of effector and "memory" NK cells following MCMV infection. Using newly-engineered transgenic mouse models, Aim 3 will address how inflammation-induced transcription factors direct NK cell function in a cell-intrinsic manner during MCMV infection. Together, the studies in this proposal will not only increase our understanding of the general molecular mechanisms whereby NK cells contribute to host defense during viral infection, but also establish novel clinical paradigms for how the NK cell compartment may be harnessed for immunization strategies against infectious disease. PUBLIC HEALTH RELEVANCE: Cytomegalovirus (CMV) can cause serious health problems and life-threatening disease in newborns and immune-suppressed individuals (including cancer and transplant patients). Using a mouse model of CMV, this proposal seeks to understand the role of opposing inflammatory cytokines and transcription factors in the natural killer (NK) cell- mediated control of viral infection. Defining the molecular mechanisms by which NK cells respond to CMV infection will potentially lead to therapeutic benefits.

描述（由申请人提供）：自然杀伤（NK）细胞是免疫系统的一个分支，特异性靶向病毒感染的宿主细胞。NK细胞最近在小鼠和人类中被证明具有新的特征，包括在病毒感染后产生免疫“记忆”的能力。人类的NK细胞缺陷由于对各种病毒感染的易感性而导致严重的健康并发症。我们的长期目标是了解NK细胞的一般生物学和这些强大的效应细胞可以介导抵抗病原体入侵的分子基础。小鼠巨细胞病毒（MCMV）感染是一个充分表征的系统，用于研究抗病毒NK细胞应答。MCMV的发病机制和该病毒采用的免疫逃避策略与人巨细胞病毒（HCMV）的特征非常相似，因此为HCMV感染提供了良好的模型，HCMV感染可导致新生儿和免疫功能低下个体的危及生命的疾病。连同仅在小鼠中可用的大量尖端免疫学工具和试剂，MCMV感染提供了用于鉴定控制NK细胞应答的激活和抑制的分子要求的强大模型。使用该模型，我们的初步研究表明，促炎细胞因子如IL-12在MCMV感染后NK细胞“记忆”的产生中起重要作用。本提案的总体目标是了解对立的促炎和抗炎细胞因子信号通路对NK细胞抗病毒感染反应的影响。目的1和2将建立在我们的初步研究结果，并调查促炎性和调节性细胞因子，和下游信号传导组件的作用，对产生效应和“记忆”NK细胞MCMV感染后。使用新工程的转基因小鼠模型，目标3将解决炎症诱导的转录因子如何在MCMV感染期间以细胞内在方式指导NK细胞功能。总之，本提案中的研究不仅将增加我们对NK细胞在病毒感染期间有助于宿主防御的一般分子机制的理解，而且还将建立新的临床范例，以了解NK细胞室如何用于对抗感染性疾病的免疫策略。 公共卫生关系：巨细胞病毒（CMV）可导致新生儿和免疫抑制个体（包括癌症和移植患者）严重的健康问题和危及生命的疾病。使用CMV的小鼠模型，该提议试图理解对抗炎性细胞因子和转录因子在自然杀伤（NK）细胞介导的病毒感染控制中的作用。确定NK细胞对CMV感染应答的分子机制将可能带来治疗益处。