SMALLPOX VIRULENCE AND COMPLEMENT REGULATORY PROTEINS

天花毒力和补体调节蛋白

• 批准号: 7641538
• 负责人: John Atkinson
• 金额: $ 38.97万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7641538
• 关键词: Active Sites; American; Amino Acids; Binding; Binding Sites; Biological Assay; CD46 Antigen; CD55 Antigens; Catalytic Domain; Cells; Complement; Complement 3b; Complement 3d Receptors; Complement 4b; Complement Activation; Complement Factor H; Complement Inactivators; Complement Receptor; Data; Data Set; Ectromelia; Eczema; Enzymes; Excision; Family; Gene Deletion; Goals; Grant; Heparin Binding; Homologous Protein; Human; Human Activities; Immune; Immune response; Immunity; Immunologic Deficiency Syndromes; Individual; Infection; Infectious Ectromelia; Label; Laboratories; Maize; Membrane; Membrane Proteins; Modeling; Mouse Pox Virus; Mouse Protein; Mouse Strains; Mus; Mutagenesis; Mutate; Mutation; Pathogenesis; Plasma Proteins; Positioning Attribute; Poxviridae; Poxviridae Infections; Proteins; Public Health; Publishing; Regulation; Relative (related person); Resistance; Role; Russia; Site; Smallpox; Smallpox Vaccine; Structure; Surface; System; Transmembrane Domain; United States; Vaccines; Vaccinia; Vaccinia virus complement-control protein; Viral; Viral Proteins; Virulence; Virulence Factors; Virus; Zea mays; analog; base; cofactor; complement 4b-binding protein; experience; functional mimics; genetic regulatory protein; genome sequencing; human disease; in vivo; inhibitor/antagonist; man; member; microorganism; novel; receptor; research study; toe corn

Public health concems have emerged regarding use of smallpox as a bioterrorist weapon since most Americans are no longer immune. Poxviruses subvert the complement system via the expression of regulatory proteins. In variola, vaccinia and ectromelia, the proteins are called SPICE (for smallpox inhibitor of complement enzymes), VCP (vaccinia virus complement control protein) and EMICE (an uncharactedzed analog in ectromelia that we have labeled "ectromelia inhibitor of complement enzymes"). These secreted virulence factors down-regulate complement activation by mimicking the functional repertoire of a family of host proteins called the Regulators of Complement Activation (RCA). The viral proteins are also structurally related to their host counterparts. Specific Aims: 1. To characterize the complement inhibitory profile of SPICE compared to its human counterparts. We will identify the principal complement-evading activity of SPICE and this will become a target for neutralization. These assessments will take place with the native soluble protein as well as after it attaches to cells via either its heparin-binding site(s) or by addition of an anchor. 2. To determine the complement regulatory sites of SPICE. These experiments will take advantage of the functional profiles (defined in Aim 1) and the sequences of active sites of RCA proteins that are homologous to corresponding regions of SPICE, VCP, and EMICE. These two sets of data provide a logical strategy for a mutational analysis to locate the active sites. 3. To characterize the complement regulatory activity of EMICE. This mousepox protein has not been evaluated for its complement inhibitory (virulence) activity. It is about 90% identical to SPICE and VCP. We will first characterize its regulatory activity for human and mouse complement. Second, we will assess its role in vivo as a virulence factor by infecting sensitive and resistant mouse strains with the ectromelia virus deleted of its complement regulator. The proposed experiments should provide novel information relative to the pathogenesis of poxvirus infections of man and mouse. Additionally, these results will serve as a guide to produce a less toxic small pox vaccine and to identify a viral target for mAb treatment of variola infection.

自1999年以来，公众对天花作为生物恐怖主义武器的使用产生了担忧