Activation of CCR2+ human proinflammatory monocytes by human herpesvirus-6B chemokine N-terminal peptide
Activation of CCR2+ human proinflammatory monocytes by human herpesvirus-6B chemokine N-terminal peptide
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DOI：
10.1099/vir.0.050153-0
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发表时间：
2013-07-01
影响因子：
3.8
通讯作者：
Gompels, U. A.
中科院分区：
文献类型：
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作者：
Clark, D. J.;Catusse, J.;Gompels, U. A.
表达带有 CD14 和 CD16 的 CCR2 的人单核细胞可以介导抗原呈递，并促进炎症、脑浸润和免疫衰老。最近发现的作用是在人类免疫缺陷病毒感染、结核病和寄生虫病中发挥作用。人类疱疹病毒 6B (HHV-6B) 编码趋化因子 U83B，它对 CCR2 具有单特异性，与相关的 HHV-6A U83A 不同，后者激活免疫效应细胞和树突状细胞上的 CCR1、CCR4、CCR5、CCR6 和 CCR8。这些差异可能会改变潜伏/裂解复制的白细胞亚群募集以及相关的神经炎症病理学。因此，U83A 和 U83B 之间的细胞相互作用可能有助于确定这些病毒之间潜在的趋向性差异。 U83A 的特异性以 38 个残基 N 端剪接截短的形式得以保留。在这里，我们试图确定趋化因子受体特异性差异的基础并确定可能的应用。为此，我们首先分析了撒哈拉以南非洲地区自然宿主种群的变异，这两种病毒在该地区同样流行，并将其与全球毒株进行了比较。对 112 个 HHV-6A 和 HHV-6B 感染中 U83 N 末端变异的分析确定了 6/38 个 U83A 或 U83B 特异性残基。我们还在一个 U83B 序列“U83BA”中发现了一个独特的单一 U83A 特异性取代。接下来，通过衍生 N 末端 (NT) 17 聚体肽并测定离体人类白细胞（天然宿主和细胞靶标）的激活来测试变异效应。 U83B-NT 可有效诱导 CCR2+ 白细胞的趋化性，但 U83BA-NT 或 U83A-NT 则不会。对 U83B-NT 激活群体的分析发现了迁移的 CCR2+ 白细胞，但没有发现 CCR5+ 白细胞。 U83BA-NT 天冬酰胺-赖氨酸 14 取代破坏了活性，从而定义了 CCR2 特异性，并作为细胞相互作用中 HHV-6A/B 差异的主要决定因素。设计了基于流式细胞术的形状变化测定，并用于提供 U83B-NT 可以激活 CCR2+CD14+CD16+ 单核细胞的进一步证据。这定义了 HHV-6A/B 疾病的潜在抗病毒靶点和促炎性单核细胞的新型肽免疫调节剂。
Human monocytes expressing CCR2 with CD14 and CD16 can mediate antigen presentation, and promote inflammation, brain infiltration and immunosenescence. Recently identified roles are in human immunodeficiency virus infection, tuberculosis and parasitic disease. Human herpesvirus 6B (HHV-6B) encodes a chemokine, U83B, which is monospecific for CCR2, and is distinct from the related HHV-6A U83A, which activates CCR1, CCR4, CCR5, CCR6 and CCR8 on immune effector cells and dendritic cells. These differences could alter leukocyte-subset recruitment for latent/lytic replication and associated neuroinflammatory pathology. Therefore, cellular interactions between U83A and U83B could help dictate potential tropism differences between these viruses. U83A specificity is maintained in the 38-residue N-terminal spliced-truncated form. Here, we sought to determine the basis for the chemokine receptor specificity differences and identify possible applications. To do this we first analysed variation in a natural host population in sub-Saharan Africa where both viruses are equally prevalent and compared these to global strains. Analyses of U83 N-terminal variation in 112 HHV-6A and HHV-6B infections identified 6/38 U83A or U83B-specific residues. We also identified a unique single U83A-specific substitution in one U83B sequence, 'U83BA'. Next, the variation effects were tested by deriving N-terminal (NT) 17-mer peptides and assaying activation of ex vivo human leukocytes, the natural host and cellular target. Chemotaxis of CCR2+ leukocytes was potently induced by U83B-NT, but not U83BA-NT or U83A-NT. Analyses of the U83B-NT activated population identified migrated CCR2+, but not CCR5+, leukocytes. The U83BA-NT asparagine-lysine14 substitution disrupted activity, thus defining CCR2 specificity and acting as a main determinant for HHV-6A/B differences in cellular interactions. A flow-cytometry-based shape-change assay was designed, and used to provide further evidence that U83B-NT could activate CCR2+CD14+CD16+ monocytes. This defines a potential antiviral target for HHV-6A/B disease and novel peptide immunomodulator for proinflammatory monocytes.