CD47 Homologues in Pathogenesis of Poxvirus Infection

描述（由申请人提供）：根据RFA AI-02-002的要求，本申请的重点是研究天花的发病机制。天花是一个主要的生物恐怖主义威胁，因为它是通过气溶胶途径感染的；一旦确定感染，它就会在人与人之间迅速传播；在未接种疫苗的人群中，它的致死率很高；而且没有有效的治疗方法。由于对天花发病机制的研究实际上早在30多年前就结束了，因此，针对这种疾病的新威胁设计新的预防或治疗方法的知识库严重过时。所有已测序的痘病毒基因组都包含一个与普遍表达的脊椎动物质膜蛋白CD47同源的开放阅读框（orf）。痘病毒表达许多与脊椎动物蛋白同源的蛋白，包括细胞因子和细胞因子受体样基因、趋化因子和趋化因子受体样基因、补体控制蛋白和TNF受体同源物。这些病毒蛋白被统称为免疫逃避蛋白，因为它们的目的是破坏正常的宿主免疫反应。此外，痘病毒表达crmA和其他蛋白质，其主要目的是抑制感染细胞的死亡。两个痘病毒蛋白家族对病毒存活、复制和传播都很重要。CD47具有几种已知的功能，使其成为病毒颠覆的理想候选者，因为它在调节吞噬作用、吞噬细胞活化和迁移、对颗粒抗原的免疫反应和淋巴细胞凋亡中发挥作用。这种应用的假设是，痘病毒基因组中与CD47同源的高度保守的开放阅读框的存在是为了破坏这些CD47的一个或多个功能，从而使病毒受益。了解这种痘病毒CD47同源物的功能可能会导致预防或治疗天花的新方法。为了了解这种痘病毒抗原的功能，我们建议鉴定与CD47同源的天花病毒和牛痘病毒抗原的宿主细胞配体，并确定天花病毒CD47同源物如何破坏正常的CD47功能。对哺乳动物CD47的这种痘病毒同源物的进一步了解将有助于阐明天花的传播和发病机制，并将有助于制定预防和治疗天花的新策略。

DESCRIPTION (provided by applicant): This application focuses on the pathogenesis of smallpox, in response to RFA AI-02-002. Smallpox is a major bioterrorism threat because it is infectious by the aerosol route; once infection is established it spreads rapidly from human to human; it has a high case fatality rate among unvaccinated individuals; and there is no effective treatment. Since research on the pathogenesis of smallpox effectively ended more than 30 years ago, the knowledge base for designing new methods for prevention or treatment in light of the new threat of this disease is woefully out of date. All sequenced poxvirus genomes contain an open reading frame (orf) homologous to the ubiquitously expressed vertebrate plasma membrane protein CD47. Poxviruses express a number of proteins homologous to vertebrate proteins, including cytokine- and cytokine receptor-like genes, chemokine- and chemokine receptor-like genes, complement control proteins, and TNF receptor homologues. These viral proteins have been collectively called immuno-evasins because of their purpose to undermine normal host immune responses. In addition poxviruses express crmA and other proteins whose main purpose is to inhibit the death of infected cells. Both families of poxvirus proteins are important for viral survival, replication, and transmission. CD47 has several known functions that make it an ideal candidate for viral subversion, since it has a role in regulation of phagocytosis, phagocyte activation and migration, immune response to particulate antigens, and apoptosis of lymphocytes. The hypothesis of this application is that the highly conserved open reading frame in poxvirus genomes homologous to CD47 exists to subvert one or more of these CD47 functions to the advantage of the virus. Understanding the functions of this poxvirus CD47 homologue could lead to new approaches to prevention or therapy of smallpox. To understand the functions of this poxvirus orf, we propose to identify host cell ligands for the Variola and Vaccinia orfs homologous to CD47 and determine how the Variola CD47 homologue subverts normal CD47 functions. This increased understanding of this poxvirus homologue of mammalian CD47 will shed light on transmission and pathogenesis of smallpox and will aid in the development of new strategies for prevention and treatment of this disease.