Viral Chemokine Alteration of Neutrophil Functions

病毒趋化因子改变中性粒细胞功能

• 批准号: 8021810
• 负责人: TIMOTHY E SPARER
• 金额: $ 30.32万
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8021810
• 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; Immunocompromised Host; In Vitro; Inbred BALB C Mice; Infection; Inflammatory; Inflammatory Response; Interleukin-8B Receptor; Knock-in Mouse; Leukocyte Trafficking; Libraries; Life Cycle Stages; Longevity; Mental Retardation; Mission; Modeling; Morbidity - disease rate; Mus; Neutrophil Activation; Normal Cell; Pathogenesis; Pathology; Patients; Pattern; Phagocytosis; Play; Porifera; Proteins; Public Health; Recombinants; Role; Signal Transduction; Site; Site-Directed Mutagenesis; Specificity; Swelling; Transgenic Organisms; Transplant Recipients; United States; United States National Institutes of Health; Variant; Viral; Viral Genes; Viral Pathogenesis; Virulence; Virulence Factors; Virulent; cell type; chemokine; chemokine receptor; combat; cytokine; fighting; fitness; flexibility; functional outcomes; hearing impairment; homologous recombination; in utero; in vivo; migration; monolayer; mouse model; neutrophil; novel; receptor; release of sequestered calcium ion into cytoplasm; response; uptake

DESCRIPTION (provided by applicant): 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, Gro1. 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. Narrative: This proposal supports the NIH mission by contributing to better public health within the United States. HCMV infection/reactivation is a leading cause of morbidity in immunocompromised hosts as well as hearing loss and mental retardation following in utero infection. Understanding an additional mechanism that HCMV exploits for dissemination/survival will provide a new avenue for exploration of novel anti-virals to combat HCMV disease in immunocompromised hosts.

描述（由申请人提供）：中性粒细胞提供了人体针对感染的第一道防线。他们通过释放趋化因子或细胞因子来抗击感染，这些因子或细胞因子引发了其他免疫介质和细胞类型的级联反应。中性粒细胞本身首先发出信号，以通过趋化因子转移到感染部位。一旦到达感染部位，中性粒细胞就会激活。这种激活可以采取多种形式：增加的胞吐和吞噬作用，其寿命的延长以及粘附分子的改变，以增强其特异性和迁移率。尽管具有讽刺意味的是，中性粒细胞的快速反应和灵活性使它们成为人体免疫系统不可或缺的一部分，但人类巨细胞病毒（HCMV）可能会使用中性粒细胞激活来获得其自身的进化优势。 HCMV可能会使用中性粒细胞进行传播，或吸引HCMV可以保持潜在的其他细胞类型。有毒的HCMV产生功能性趋化因子VCXCL-1TOL，可以通过吸引和激活嗜中性粒细胞来模仿人体的正常免疫反应，但该趋化因子仅与宿主ELR-CXC趋化因子GRO1相同22％。该病毒趋化因子的基因是HCMV基因组中最可变的基因之一，来自不同分离株的VCXCL-1蛋白彼此具有32％的身份。使用来自移植患者的病毒趋化因子和AIDS患者，我们将将这些病毒趋化因子与毒气和减弱CMV菌株的趋化因子进行比较。我们将要解决的问题是：1）这些病毒趋化因子是否具有独特的结合和功能结果？ 2）这些差异是否与体内病毒发病机理有关？我们已经从代表VCXCL-1家族中差异的四个不同临床分离株中表达并分离了VCXCL-1蛋白。我们的下一步将是评估病毒趋化因子受体使用，结合和信号传导特征以及细胞过程的差异。最初，我们将重点关注C956菌株的变异趋化因子，该趋化因子与VCXCL-1TOL具有最小同源性和无毒Towne菌株的趋化因子。然后，我们将这些蛋白质在使用鼠CMV作为HCMV趋化因子基因的替代物中所起的作用将这些体外差异与这些蛋白质在病毒传播和发病机理中的作用联系起来。通过了解这些新型病毒趋化因子如何在体外和体内发挥作用，我们将开始更多地了解CMV生命周期之间的复杂关系，其对中性粒细胞功能和疾病的影响。叙述：该提案通过为美国境内的更好的公共卫生做出贡献来支持NIH任务。 HCMV感染/重新激活是免疫功能低下的宿主发病的主要原因，以及子宫感染后的听力丧失和智力低下。了解HCMV利用用于传播/生存的另一种机制将为探索新型抗病毒物的新途径，以打击免疫功能低下的宿主中的HCMV疾病。