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可能在儿童风湿病的发病和发病机制中所起的作用。自然杀伤（NK）细胞是细胞毒性淋巴细胞，在先天免疫应答病毒感染中起核心作用。它们在介导对大型DNA病毒（如疱疹病毒）的抗性方面尤其重要。最近的研究已经清楚地证明了这一点，鉴定了特定的小鼠NK细胞激活受体及其病毒编码配体，这些配体负责小鼠对疱疹病毒，小鼠巨细胞病毒的抗性。对另一大类DNA病毒——痘病毒的抗性似乎也是由NK细胞介导的。本研究的重点是利用痘病毒牛痘作为模型，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。申请人与其导师Wayne Yokoyama进行的初步工作表明，NK细胞参与赋予小鼠对牛痘感染的抵抗力。本课题的具体目的是：1)表征牛痘诱导NK细胞活化和增殖的细胞因子，2)鉴定介导牛痘抗性的小鼠NK细胞活化受体，3)评估该受体在提供牛痘体内抗性中的作用。申请人是一名拥有化学工程博士学位的内科医生，正在华盛顿大学医学院完成儿科风湿病学/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，旨在促进申请人过渡到独立研究人员的职业生涯。提议的工作将在Wayne Yokoyama博士的指导下进行，Wayne Yokoyama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。

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.