Viral Chemokine Alteration of Neutrophil Functions

中性粒细胞是人体抵御感染的第一道防线。他们打架 感染，尤其是通过释放趋化因子或细胞因子来启动 其他免疫介质和细胞类型的级联。中性粒细胞本身是第一个 通过趋化因子发出移动到感染部位的信号。一旦他们到达感染的地方 中性粒细胞被激活。这种激活可以有多种形式：增加 胞吐和吞噬、延长寿命和改变黏附 用于增强其特异性和流动性的分子。尽管快速的反应和 中性粒细胞的灵活性使其成为人体免疫系统的组成部分，人类 具有讽刺意味的是，巨细胞病毒(HCMV)本身可能会激活中性粒细胞。 进化优势。人巨细胞病毒可利用中性粒细胞进行传播或吸引 其他类型的细胞中，人巨细胞病毒可以保持潜伏。强毒巨细胞病毒产生一种 功能性趋化因子vCXCL-1Tol，可以模拟人体的正常免疫反应 通过吸引和激活中性粒细胞，这种趋化因子只与 宿主ELR-CXC趋化因子，组。这种病毒趋化因子的基因是最多的 不同分离株的vCXCL-1蛋白在HCMV基因组中的变异 彼此之间只有32%的同一性。使用来自移植患者的病毒趋化因子 和艾滋病患者，我们将比较这些病毒趋化因子和来自毒力的趋化因子 并使CMV株系减毒。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 来自四个不同的临床分离株，代表了vCXCL-1家族的差异。我们的 下一步将评估病毒趋化因子受体使用、结合和 信号特征和细胞过程。最初，我们将重点放在变体上 与vCXCL-1Tol同源性最低的C956菌株的趋化因子，以及 来自无毒的汤恩菌株的趋化因子。然后我们将把这些体外差异联系起来。 这些蛋白在病毒传播和致病中所起的作用 巨细胞病毒作为巨细胞病毒趋化因子基因的替代物。通过理解这些小说是如何 病毒趋化因子在体外和体内的作用，我们将开始了解更多关于 巨细胞病毒的生命周期、其对中性粒细胞功能的影响、 和疾病。

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.