Viral Chemokine Alteration of Neutrophil Functions

病毒趋化因子改变中性粒细胞功能

• 批准号: 8233352
• 负责人: TIMOTHY E SPARER
• 金额: $ 27.73万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 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 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233352
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adhesions; Apoptosis; Attenuated; Binding; Biological Process; Biological Response Modifiers; Body part; CXC Chemokines; Cell Adhesion Molecules; Cell physiology; Characteristics; Clinical; Collaborations; Complex; Cytomegalovirus; Cytomegalovirus Infections; Disease; Exocytosis; Family; Genes; Genome; Human; IL8 gene; IL8RA gene; IL8RB gene; Immune response; Immune system; In Vitro; Inbred BALB C Mice; Infection; Inflammatory; Inflammatory Response; Interleukin-8B Receptor; Knock-in Mouse; Leukocyte Trafficking; Libraries; Life Cycle Stages; Longevity; Modeling; Mus; Neutrophil Activation; Normal Cell; Pathogenesis; Pathology; Patients; Pattern; Phagocytosis; Play; Porifera; Proteins; Recombinants; Role; Signal Transduction; Site; Site-Directed Mutagenesis; Specificity; Swelling; Transgenic Organisms; Transplant Recipients; Variant; Viral; Viral Genes; Viral Pathogenesis; Virulence; Virulence Factors; Virulent; cell type; chemokine; chemokine receptor; cytokine; fighting; fitness; flexibility; functional outcomes; homologous recombination; in vivo; migration; monolayer; mouse model; neutrophil; novel; receptor; release of sequestered calcium ion into cytoplasm; response; uptake

Neutrophils provide the body's first line of defense against infection. They fight infections by, among other things, releasing chemokines or cytokines which initiate cascades of other immune mediators and cell types. Neutrophils themselves are first signaled to move to the site of infection via chemokines. Once they arrive at the infection site, the neutrophils are activated. This activation can take many forms: increased exocytosis and phagocytosis, extension of their life span, and alteration of adhesion molecules for enhancing their specificity and mobility. Although the rapid response and flexibility of neutrophils make them an integral part of the body's immune system, human cytomegalovirus (HCMV), ironically, may use neutrophil activation for its own evolutionary advantage. HCMV may use neutrophils for dissemination or for attracting other cell types within which HCMV can remain latent. Virulent HCMV produces a functional chemokine, vCXCL-1Tol, that can mimic the body's normal immune response by attracting and activating neutrophils, yet this chemokine is only 22% identical to the host ELR-CXC chemokine, Groα. The gene for this viral chemokine is one of the most variable in the HCMV genome with the vCXCL-1 proteins from different isolates having as little as 32% identity with each other. Using viral chemokines from a transplant patient and AIDS patients, we will compare these viral chemokines to chemokines from virulent and attenuated CMV strains. The questions that we will address are: 1) Do these viral chemokines have unique binding and functional outcomes? 2) Do these differences relate to viral pathogenesis in vivo? We have expressed and isolated the vCXCL-1 proteins from four different clinical isolates representing divergence in the vCXCL-1 family. Our next step will be to assess the differences in viral chemokine receptor usage, binding and signaling characteristics, and cellular processes. Initially we will focus on the variant chemokine from the C956 strain, which has the least homology to vCXCL-1Tol and the chemokine from the avirulent Towne strain. We will then relate these in vitro differences to the role that these proteins play in viral dissemination and pathogenesis using murine CMV as a surrogate for the HCMV chemokine genes. By understanding how these novel viral chemokines function in vitro and in vivo, we will begin to understand more about the complex relationship between the CMV life cycle, its impact on neutrophil functions, and disease.

中性粒细胞是人体抵御感染的第一道防线。他们打架 通过释放趋化因子或细胞因子， 其他免疫介质和细胞类型的级联。中性粒细胞本身首先是 通过趋化因子向感染部位移动。一旦他们到达感染点 中性粒细胞被激活。这种激活可以采取多种形式： 胞吐作用和吞噬作用，延长其寿命，改变粘附 分子以增强其特异性和流动性。虽然快速反应和 中性粒细胞的灵活性使它们成为人体免疫系统的一个组成部分， 具有讽刺意味的是，巨细胞病毒（HCMV）可能利用中性粒细胞活化来实现其自身的功能。 进化优势HCMV可利用中性粒细胞传播或吸引 其他细胞类型，其中HCMV可以保持潜伏。毒力巨细胞病毒产生 一种功能性趋化因子vCXCL-1 Tol，可以模拟人体的正常免疫反应 通过吸引和激活嗜中性粒细胞，然而这种趋化因子只有22%相同， 宿主ELR-CXC趋化因子，Gro.这种病毒趋化因子的基因是最重要的基因之一 与来自不同分离株的vCXCL-1蛋白相比， 只有32%的人是同一的使用移植病人的病毒趋化因子 和艾滋病患者，我们将比较这些病毒趋化因子， 和减毒CMV菌株。我们要解决的问题是：1）这些病毒 趋化因子具有独特的结合和功能结果？2)这些差异是否与 病毒在体内的致病机制我们表达并分离了vCXCL-1蛋白 来自代表vCXCL-1家族分歧的四种不同临床分离株。我们 下一步将是评估病毒趋化因子受体的使用，结合和 信号特征和细胞过程。首先，我们将重点放在变体上 来自C956菌株的趋化因子，其与vCXCL-1 Tol具有最小同源性，并且 来自无毒汤尼菌株的趋化因子然后我们将这些体外差异 这些蛋白质在病毒传播和发病机制中的作用， CMV作为HCMV趋化因子基因的替代物。通过了解这些小说 病毒趋化因子在体外和体内的功能，我们将开始了解更多关于 CMV生命周期，其对中性粒细胞功能的影响， 和疾病