Regulation of immune response to influenza by innate immunity.

描述(由申请人提供)：流感病毒是一个主要的世界性健康问题，也是用于生物恐怖主义的潜在媒介。在已知的3种毒株中，甲型流感可能是研究得最好的，因为它不仅感染人类，还感染其他哺乳动物，并且可以适应动物模型。主要的抗原靶--血凝素和神经氨酸酶--会发生结构变化，因此针对一种毒株形成的抗体通常不会对相关毒株产生保护作用。由于这种“抗原变异”，中和抗体不会持续很久，需要每年接种一次疫苗。细胞毒性T细胞对更保守的核衣壳等核心蛋白的反应；或者针对外层蛋白保守区域的抗体将是产生长期记忆反应的理想靶点。该项目的总体目标是研究先天免疫(补体系统和天然免疫球蛋白M)在流感特异性效应细胞和记忆性T和B细胞发育中的作用的细胞和分子机制。提出了三个具体目标：(I)研究补体C3在流感特异性效应细胞和记忆性CDS T细胞激活和扩张中的作用。(Ii)研究补体C3在记忆B细胞发育中的作用；(Iii)研究天然免疫球蛋白M在宿主对流感的先天和适应性反应中的作用。

DESCRIPTION (provided by applicant): Influenza virus represents a major worldwide health problem as well as a potential agent for use in bioterrorism. Of the 3 known strains, influenza A is probably the best studied as it infects not only humans but other mammals and can be adapted to animal models. The major antigenic targets-hemagglutinin and neuraminidase- undergo structural changes such that antibodies formed against one strain generally are not protective with a related strain. Because of this "antigenic variation", neutralizing antibodies are not long lasting and necessitate annual vaccination. A cytotoxic T cell response to inner core proteins such as the nucleocapsid that are more conserved; or a antibody that targets conserved regions of the outer coat proteins would be desirable targets for generation of long lasting memory responses. The overall goal of this project is to investigate the cellular and molecular mechanisms underlying the role for innate immunity (complement system and natural IgM) in development of influenza-specific effector and memory T and B cells. Three specific aims are proposed: (i) Examine the role of complement C3 in the activation and expansion of influenza-specific effector and memory CDS T cells. (ii) Examine the role of complement C3 in the development of memory B cells, (iii) Examine the role of natural IgM in host innate and adaptive response to influenza.