Determinanats of Protective Immunity to Metapneumovirus

应聘者描述(由申请人提供)：作为一名内科科学家，应聘者的长期职业目标是对人类对病毒的免疫反应的分子基础进行研究人员发起的研究。近期目标包括获得分子病毒学和动物免疫学研究方面的技能。这些技能对于补充应聘者在分子人类免疫学方面的广泛培训至关重要，这些培训是在之前研究人类对呼吸道合胞病毒(RSV)的抗体反应时获得的。在这个项目中获得的经验将广泛地为候选人进行儿童早期病原体的免疫生物学的独特研究做好准备。人类偏肺病毒(HMPV)是一种新发现的副粘病毒，可在5岁前感染大多数人。我们的初步数据表明，hMPV是儿童下呼吸道感染(LRI)的主要原因，其疾病谱和发病率与RSV相似。这项工作建议定义hMPV保护性免疫的抗原决定簇，为宿主对这种重要的新兴病原体的免疫反应提供基础的新知识。这一建议的中心假设是hMPV表面糖蛋白F(融合)和G(附着)是保护性免疫的主要决定因素，保护是由体液抗体介导的。具体目的#1是研究在基于痘苗病毒的新型哺乳动物系统中表达的hMPV F和G蛋白的抗体反应。这些重组抗原将成为评估宿主对hMPV免疫应答的重要工具。目的2确定重组痘苗病毒表达的hMPV F和G表面蛋白是否是啮齿动物模型的主要保护性抗原。这些实验将确定保护性免疫的决定因素，并确定hMPV毒株之间的抗原多样性。具体目的#3是确定仅体液抗体是否足以介导对hMPV引起的复发LRI的保护作用。这项工作将提供关于宿主对一种重要的儿童呼吸道病原体的免疫反应的有价值的新数据，这将适用于与hMPV感染相关的人类免疫病理学研究。保护性免疫机制的阐明也将对未来潜在疫苗的开发具有重要意义。拟议的工作将提供候选人的技能和经验，成为人类病毒免疫学领域的杰出内科科学家。

DESCRIPTION (provided by applicant): The candidate's long-term career goal as a physician-scientist is to conduct investigator-initiated research into the molecular basis of the human immune response to viruses. Immediate goals include acquisition of skills in molecular virology and immunology studies in animals. These skills are critical to complement the candidate's extensive training in molecular human immunology acquired during previous studies of the human antibody response to respiratory syncytial virus (RSV). The experience gained during this project will prepare the candidate broadly to conduct unique studies of the immunobiology of early childhood pathogens. Human metapneumovirus (hMPV) is a newly described paramyxovirus that infects most humans by the age of five years. Our preliminary data indicate that hMPV is a major cause of lower respiratory tract infection (LRI) in children with a spectrum of illness and morbidity similar to that of RSV. This work proposes to define the antigenic determinants of protective immunity to hMPV, providing foundational new knowledge about the host immune response to this important emerging pathogen. The central hypothesis of this proposal is that the hMPV surface glycoproteins F (fusion) and G (attachment) are the major determinants of protective immunity and that protection is mediated by humoral antibody. Specific aim #1 is to investigate the antibody response to hMPV F and G proteins expressed in a novel vaccinia-virus based mammalian system. These recombinant antigens will be critical tools to evaluate the host immune response to hMPV. Specific aim #2 is to determine whether hMPV F and G surface proteins expressed by recombinant vaccinia virus are major protective antigens in a rodent model. These experiments will identify the determinants of protective immunity and define antigenic diversity between hMPV strains. Specific aim # 3 is to determine if humoral antibody alone is sufficient to mediate protection against recurrent LRI caused by hMPV. This work will provide valuable new data regarding the host immune response to an important respiratory pathogen of childhood that will be applicable to studies of human immunopathology associated with hMPV infection. The elucidation of the mechanism of protective immunity will also be important for future development of potential vaccines. The proposed work will provide the candidate skills and experience to be an outstanding physician-scientist in the field of human viral immunology.