Novel Human Cytomegalovirus Viral Chemokines, vCXCL-1s, Display Functional Selectivity for Neutrophil Signaling and Function.
Novel Human Cytomegalovirus Viral Chemokines, vCXCL-1s, Display Functional Selectivity for Neutrophil Signaling and Function.
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DOI：
10.4049/jimmunol.1400291
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发表时间：
2015-07-01
期刊：
影响因子：
--
通讯作者：
Sparer TE
中科院分区：
文献类型：
--
作者：
Heo J;Dogra P;Masi TJ;Pitt EA;de Kruijf P;Smit MJ;Sparer TE
人巨细胞病毒（HCMV）利用造血系统的成员，包括中性粒细胞，在全身传播。HCMV编码一种病毒趋化因子vCXCL-1，推测其吸引中性粒细胞在宿主内传播。编码vCXCL-1的基因UL 146是HCMV基因组中最可变的基因之一。为什么HCMV进化出这种高变异性以及这如何影响病毒的传播/发病机制尚不清楚。由于vCXCL-1高变映射到重要的结合和激活结构域，我们假设vCXCL-1 s差异激活中性粒细胞，这可能有助于HCMV传播和/或发病机制。为了测试这些病毒趋化因子是否影响中性粒细胞功能，我们从HCMV先天性感染婴儿的临床分离株中产生了11个不同分支的vCXCL-1蛋白。尽管对CXCR 1和CXCR 2受体的亲和力存在差异，但所有vCXCL-1均能够在100 nM浓度下诱导人外周血中性粒细胞（PBN）上的钙通量和整合素表达。事实上，它们对CXCR 1或CXCR 2的亲和力与趋化性、G蛋白依赖性和非依赖性（β-arrestin 2）活化或次级趋化因子（CCL 22）表达无直接相关性。我们的数据表明，vCXCL-1多态性影响结合亲和力，受体的使用，和差异PBN激活，可能有助于HCMV传播和/或发病机制。
Human cytomegalovirus (HCMV) uses members of the hematopoietic system including neutrophils for dissemination throughout the body. HCMV encodes a viral chemokine, vCXCL-1, that is postulated to attract neutrophils for dissemination within the host. The gene encoding vCXCL-1, UL146, is one of the most variable genes in the HCMV genome. Why HCMV has evolved this hypervariability and how this affects the virus’ dissemination/pathogenesis is unknown. Because the vCXCL-1 hypervariability maps to important binding and activation domains, we hypothesized that vCXCL-1s differentially activate neutrophils, which could contribute to HCMV dissemination and/or pathogenesis. In order to test whether these viral chemokines affect neutrophil function, we generated vCXCL-1 proteins from 11 different clades from clinical isolates from HCMV-congenitally infected infants. All vCXCL-1s were able to induce calcium flux at a concentration of 100 nM and integrin expression on human peripheral blood neutrophils (PBNs) in spite of differences in affinity for the CXCR1 and CXCR2 receptors. In fact their affinity for CXCR1 or CXCR2 did not directly correlate with chemotaxis, G protein-dependent and independent (β-arrestin2) activation, or secondary chemokine (CCL22) expression. Our data suggest that vCXCL-1 polymorphisms impact the binding affinity, receptor usage, and differential PBN activation that could contribute to HCMV dissemination and/or pathogenesis.
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DOI：
10.1126/science.1185350
发表时间：
2010-04-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hansen SG;Powers CJ;Richards R;Ventura AB;Ford JC;Siess D;Axthelm MK;Nelson JA;Jarvis MA;Picker LJ;Früh K
通讯作者：
Früh K
影响因子：
7.3
作者：
Hall, DA;Beresford, IJM;Giles, H
通讯作者：
Giles, H
影响因子：
5
作者：
Del Prete, G
通讯作者：
Del Prete, G
影响因子：
3.8
作者：
Dolan, A;Cunningham, C;Davison, AJ
通讯作者：
Davison, AJ
影响因子：
4.4
作者：
Godaly, G;Hang, L;Svanborg, C
通讯作者：
Svanborg, C