Oligonucleotide Motifs That Disappear during the Evolution of Influenza Virus in Humans Increase Alpha Interferon Secretion by Plasmacytoid Dendritic Cells
Oligonucleotide Motifs That Disappear during the Evolution of Influenza Virus in Humans Increase Alpha Interferon Secretion by Plasmacytoid Dendritic Cells
复制标题
DOI：
10.1128/jvi.01908-10
复制
发表时间：
2011-04-01
影响因子：
5.4
通讯作者：
Bhardwaj, Nina
中科院分区：
文献类型：
--
作者：
Jimenez-Baranda, Sonia;Greenbaum, Benjamin;Bhardwaj, Nina
A/U背景下的CpG基序在人类病毒进化过程中已优先从经典H1N1流感病毒基因组中消除。目前工作的假设是尿嘧啶背景下的CpG基序代表具有诱导免疫应答能力的序列模式，并且避免这种免疫刺激信号是观察到的优先下降的原因。为了分析这些结构域的免疫原性，我们使用浆细胞样树突状细胞（pDC）。pDC表达模式识别受体，包括Toll样受体7（TLR 7），其识别富含鸟苷和尿苷的病毒单链RNA（ssRNA），包括流感病毒ssRNA。通过TLR 7的信号传导导致炎性细胞因子和I型干扰素（IFN-I）的诱导，这是诱导特异性适应性免疫应答和建立由IFN-a介导的稳健的抗病毒应答的必要过程。IFN-α的分泌也与其他免疫细胞的激活有关，可能会放大初始IFN-α分泌的效果。因此，我们还研究了IFN-α驱动的NK细胞活化作为病毒基因组上选择性压力的另一个来源的作用。我们发现了直接的证据表明，在富含U的背景下，CpG RNA基序控制pDC活化和IFN-α驱动的NK细胞活化，可能是通过TLR 7。这些数据为禽流感病毒在适应哺乳动物宿主时丢失CpG基序提供了一个潜在的解释。由U/A包围的CpG基序的选择性减少可能是病毒避免免疫识别的策略，这一策略可能是高表达的人类免疫基因所共有的。
CpG motifs in an A/U context have been preferentially eliminated from classical H1N1 influenza virus genomes during virus evolution in humans. The hypothesis of the current work is that CpG motifs in a uracil context represent sequence patterns with the capacity to induce an immune response, and the avoidance of this immunostimulatory signal is the reason for the observed preferential decline. To analyze the immunogenicity of these domains, we used plasmacytoid dendritic cells (pDCs). pDCs express pattern recognition receptors, including Toll-like receptor 7 (TLR7), which recognizes guanosine-and uridine-rich viral single-stranded RNA (ssRNA), including influenza virus ssRNA. The signaling through TLR7 results in the induction of inflammatory cytokines and type I interferon (IFN-I), an essential process for the induction of specific adaptive immune responses and for mounting a robust antiviral response mediated by IFN-alpha. Secretion of IFN-alpha is also linked to the activation of other immune cells, potentially amplifying the effect of an initial IFN-alpha secretion. We therefore also examined the role of IFN-alpha-driven activation of NK cells as another source of selective pressure on the viral genome. We found direct evidence that CpG RNA motifs in a U-rich context control pDC activation and IFN-alpha-driven activation of NK cells, likely through TLR7. These data provide a potential explanation for the loss of CpG motifs from avian influenza viruses as they adapt to mammalian hosts. The selective decrease of CpG motifs surrounded by U/A may be a viral strategy to avoid immune recognition, a strategy likely shared by highly expressed human immune genes.