Natural Killer Cell Mediated Control of Vaccinia Virus

描述(由申请人提供)：申请人的长期目标是了解对病毒感染的异常或不足的先天免疫反应在儿童风湿病的发生和发病机制中可能起到的作用。自然杀伤(NK)细胞是一种细胞毒性淋巴细胞，在对病毒感染的先天免疫反应中发挥核心作用。它们在介导对疱疹病毒等大型DNA病毒的耐药性方面尤为重要。最近的工作已经清楚地证明了这一点，即识别特定的小鼠NK细胞激活受体及其病毒编码的配体，该配体负责小鼠对疱疹病毒-小鼠巨细胞病毒的抵抗力。对另一大类DNA病毒--痘病毒的抗药性似乎也是由NK细胞介导的。这项建议的重点是使用痘病毒，痘苗病毒，作为一个模型，研究体内的反应，先天免疫系统，特别是自然杀伤细胞对痘病毒感染。申请者与他的导师韦恩·横山进行的初步工作表明，NK细胞参与了小鼠对牛痘感染的抵抗力。该方案的具体目的是：1)鉴定参与牛痘病毒诱导的NK细胞活化和增殖的细胞因子；2)鉴定参与介导对牛痘病毒的抗性的小鼠NK细胞激活受体；3)评估该受体在体内提供对牛痘病毒的抗性中的作用。申请者是一名拥有化学工程博士学位的内科医生，即将完成他在华盛顿大学医学院的儿科风湿病/免疫学研究员培训。本提案中的工作是五年职业发展计划的一部分，以促进申请人过渡到独立研究人员的职业生涯。拟议的工作将在韦恩·横山博士的指导下进行，他是NK细胞领域公认的先驱，成功地培训了许多研究生和博士后研究员。

DESCRIPTION (provided by applicant): The applicant's long-term goal is to understand the role that an abnormal or inadequate innate immune response to viral infections may play in the initiation and pathogenesis of pediatric rheumatological diseases. Natural killer (NK) cells are cytotoxic lymphocytes that play a central role in the innate immune response to viral infections. They are particularly important in mediating resistance to large DNA viruses such as herpesviruses. This has been clearly demonstrated by recent work identifying the specific murine NK cell activation receptor and its virally encoded ligand responsible for resistance of mice to the herpesvirus, murine cytomegalovirus. Resistance to another family of large DNA viruses, the poxviruses, also appears to be mediated by NK cells. This proposal focuses on using the poxvirus, vaccinia, as a model for studying the in vivo responses of the innate immune system and specifically NK cells to poxvirus infections. Preliminary work performed by the applicant with his mentor, Wayne Yokoyama, suggests that NK cells are involved in conferring resistance to vaccinia infection in mice. The specific aims of this proposal are: 1) to characterize the cytokines involved in vaccinia-induced NK cell activation and proliferation, 2) to identify the murine NK cell activation receptor involved in mediating resistance to vaccinia, and 3) to evaluate the role of this receptor in providing in vivo resistance to vaccinia. The applicant is a physician with a Ph.D. in Chemical Engineering who is completing his fellowship training in Pediatric Rheumatology/lmmunology at Washington University School of Medicine. The work in this proposal is part of five-year career development plan to facilitate the applicant's transition to a career as an independent researcher. The proposed work will occur under the mentorship of Dr. Wayne Yokoyama a recognized pioneer in the NK cell field who has successfully trained numerous graduate students and postdoctoral fellows.