Natural Killer Cell Mediated Control of Vaccinia Virus

描述（由申请方提供）：申请方的长期目标是了解对病毒感染的先天免疫应答异常或不足在儿科风湿性疾病的发生和发病机制中可能发挥的作用。 自然杀伤（NK）细胞是细胞毒性淋巴细胞，其在对病毒感染的先天免疫应答中发挥核心作用。它们在介导对大DNA病毒如疱疹病毒的抗性方面特别重要。这已经通过最近的工作明确证明，鉴定了特异性鼠NK细胞活化受体及其病毒编码的配体，其负责小鼠对疱疹病毒、鼠巨细胞病毒的抗性。对另一个大型DNA病毒家族痘病毒的抗性似乎也是由NK细胞介导的。该建议的重点是使用痘病毒，牛痘，作为研究先天免疫系统，特别是NK细胞对痘病毒感染的体内反应的模型。申请人与他的导师韦恩横山进行的初步工作表明，NK细胞参与赋予小鼠对牛痘感染的抗性。该提议的具体目的是：1）表征参与牛痘诱导的NK细胞活化和增殖的细胞因子，2）鉴定参与介导牛痘抗性的鼠NK细胞活化受体，和3）评价该受体在提供体内牛痘抗性中的作用。申请人是一名医生，拥有博士学位。他正在华盛顿大学医学院完成儿科流变学/免疫学的奖学金培训。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，横山博士是NK细胞领域公认的先驱，他成功地培养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.