The natural killer cell response against mouse cytomegalovirus infection

描述(由申请人提供)：自然杀伤(NK)细胞组成免疫系统的一只手臂，专门针对感染病毒的宿主细胞。最近在小鼠和人类身上证明了NK细胞具有新的特征，包括在病毒感染后产生免疫“记忆”的能力。由于对各种病毒感染的易感性，人类的NK细胞缺乏会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，以及这些强大的效应细胞可以介导对病原体入侵的保护的分子基础。小鼠巨细胞病毒(MCMV)感染是研究抗病毒NK细胞反应的重要手段。MCMV的致病机制和免疫逃避策略与人类巨细胞病毒(HCMV)的特征非常相似，从而为HCMV感染提供了一个很好的模型。HCMV感染会导致新生儿和免疫功能低下的人患上危及生命的疾病。与大量仅在小鼠身上可用的尖端免疫学工具和试剂一起，MCMV感染为确定控制NK细胞反应的激活和抑制的分子要求提供了一个强大的模型。利用这一模型，我们的初步研究表明，促炎症细胞因子，如IL-12，在MCMV感染后NK细胞“记忆”的产生中起重要作用。这项建议的总体目标是了解相反的促炎和抗炎细胞因子信号通路对NK细胞对抗病毒感染的反应的影响。AIMS 1和AIMS 2将以我们的初步发现为基础，研究促炎症和调节细胞因子以及下游信号成分在MCMV感染后效应和“记忆”NK细胞生成中的作用。利用新设计的转基因小鼠模型，AIM 3将研究炎症诱导的转录因子如何在MCMV感染过程中以细胞固有的方式指导NK细胞发挥功能。总之，这项建议中的研究不仅将增加我们对NK细胞在病毒感染过程中帮助宿主防御的一般分子机制的理解，而且还将为如何利用NK细胞亚群来对抗传染病的免疫策略建立新的临床范例。

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.