Catusse Julie, Spinks Jenny, Mattick Claire, Dyer Angela, Laing Ken, Fitzsimons Carlos, Smit Martine J, Gompels Ursula A
Department of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, University of London, London, UK.
Eur J Immunol. 2008 Mar;38(3):763-77. doi: 10.1002/eji.200737618.
Human herpesvirus-6A (HHV-6A) betachemokine-receptor U51A binds inflammatory modulators CCL2, CCL5, CCL11, CCL7, and CCL13. This unique specificity overlaps that of human chemokine receptors CCR1, CCR2, CCR3, and CCR5. In model cell lines, expression leads to CCL5 down-regulation with both constitutive and inducible signaling. Here, immunomodulation pathways are investigated in human leukocytes permissive for infection. Constitutive signaling was shown using inositol phosphate assays and inducible calcium signaling by response to CCL2, CCL5 and CCL11. Constitutive signaling targets were examined using an immune response-related microarray and RT-PCR, showing down-regulation of CCL5 and FOG-2, a hematopoietic transcriptional repressor. By RT-PCR and siRNA reversion, CCL5 and FOG-2 were shown down-regulated, during peak U51A expression post infection. Two further active ligands, XCL1 and CCL19, were identified, making U51A competitor to their human receptors, XCR1 and CCR7, on T lymphocytes, NK and dendritic cells. Finally, U51A-expressing cell lines and infected ex vivo leukocytes, showed migration towards chemokine-gradients, and chemokine internalization. Consequently, U51A may affect virus dissemination or host transmission by chemotaxis of infected cells to sites of chemokine secretion specific for U51A (for example the lymph node or lung, by CCL19 or CCL11, respectively) and evade immune-effector cells by chemokine diversion and down-regulation, affecting virus spread and inflammatory pathology.
人类疱疹病毒6A（HHV-6A）β趋化因子受体U51A可结合炎症调节因子CCL2、CCL5、CCL11、CCL7和CCL13。这种独特的特异性与人类趋化因子受体CCR1、CCR2、CCR3和CCR5的特异性重叠。在模型细胞系中，其表达通过组成型和诱导型信号传导导致CCL5下调。在此，对允许感染的人类白细胞中的免疫调节途径进行了研究。使用肌醇磷酸测定法显示组成型信号传导，并通过对CCL2、CCL5和CCL11的反应显示诱导型钙信号传导。使用与免疫反应相关的微阵列和RT-PCR检查组成型信号传导靶点，结果显示CCL5和造血转录抑制因子FOG-2下调。通过RT-PCR和siRNA逆转，发现在感染后U51A表达高峰期CCL5和FOG-2下调。还鉴定出另外两种活性配体XCL1和CCL19，这使得U51A在T淋巴细胞、自然杀伤细胞和树突状细胞上成为其人类受体XCR1和CCR7的竞争者。最后，表达U51A的细胞系和体外感染的白细胞显示出向趋化因子梯度的迁移以及趋化因子内化。因此，U51A可能通过将感染细胞趋化至对U51A特异的趋化因子分泌部位（例如分别通过CCL19或CCL11趋化至淋巴结或肺）来影响病毒传播或宿主传播，并通过趋化因子转移和下调来逃避免疫效应细胞，从而影响病毒传播和炎症病理。
