Determinanats of Protective Immunity to Metapneumovirus

描述（由申请人提供）：作为一名内科科学家，候选人的长期职业目标是对人类对病毒免疫反应的分子基础进行研究者发起的研究。近期目标包括获得动物分子病毒学和免疫学研究的技能。这些技能对于补充候选人在先前对呼吸道合胞病毒（RSV）的人类抗体反应的研究中获得的广泛的人类分子免疫学培训至关重要。在这个项目中获得的经验将为候选人进行早期儿童病原体免疫生物学的独特研究做准备。人偏肺病毒（hMPV）是一种新发现的副粘病毒，大多数人在5岁前感染。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，其疾病谱系和发病率与RSV相似。这项工作提出了确定hMPV保护性免疫的抗原决定因素，为宿主对这一重要新兴病原体的免疫反应提供了基础的新知识。该建议的中心假设是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，并且保护是由体液抗体介导的。具体目的#1是研究在一种新的基于牛痘病毒的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免疫反应的重要工具。具体目的#2是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中的主要保护性抗原。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是确定体液抗体单独是否足以介导对hMPV引起的复发性LRI的保护。这项工作将为宿主对一种重要的儿童呼吸道病原体的免疫反应提供有价值的新数据，这将适用于与hMPV感染相关的人类免疫病理学研究。阐明保护性免疫的机制对未来潜在疫苗的开发也具有重要意义。建议的工作将提供候选人的技能和经验，成为一个杰出的内科科学家在人类病毒免疫学领域。

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.