Elevation of CpG frequencies in influenza A genome attenuates pathogenicity but enhances host response to infection.
Elevation of CpG frequencies in influenza A genome attenuates pathogenicity but enhances host response to infection.
复制标题
DOI：
10.7554/elife.12735
复制
发表时间：
2016-02-16
期刊：
影响因子：
7.7
通讯作者：
Simmonds P
中科院分区：
文献类型：
--
作者：
Gaunt E;Wise HM;Zhang H;Lee LN;Atkinson NJ;Nicol MQ;Highton AJ;Klenerman P;Beard PM;Dutia BM;Digard P;Simmonds P
先前，我们证明了CpG和UpA二核苷酸的频率深刻地影响埃可病毒7的复制能力（Tulloch等人，2014年）。在这里，我们表明，甲型流感病毒（IAV）与最大化的频率，这些二核苷酸在第5节显示出可比的衰减在细胞培养物相比，未经修改的病毒和置换的控制（CDLR）。在体内也表现出减毒，在用200 PFU的CpG-高和UpA-高突变体感染的小鼠的肺中病毒载量降低10-100倍。然而，两者都诱导了强大的炎症细胞因子和适应性（T细胞和中和抗体）反应，与它们的复制不成比例。CpG-高感染的小鼠还显示出显著降低的临床严重程度、最小的体重减轻和肺中降低的免疫病理学，然而在用该突变体进行低剂量（20 PFU）预免疫后实现了对致死剂量WT攻击的无菌免疫。增加CpG二核苷酸频率代表了用于产生安全、高免疫反应性疫苗的通用且潜在高效的方法。DOI：http://dx.doi.org/10.7554/eLife.12735.001网站
Previously, we demonstrated that frequencies of CpG and UpA dinucleotides profoundly influence the replication ability of echovirus 7 (Tulloch et al., 2014). Here, we show that that influenza A virus (IAV) with maximised frequencies of these dinucleotides in segment 5 showed comparable attenuation in cell culture compared to unmodified virus and a permuted control (CDLR). Attenuation was also manifested in vivo, with 10-100 fold reduced viral loads in lungs of mice infected with 200PFU of CpG-high and UpA-high mutants. However, both induced powerful inflammatory cytokine and adaptive (T cell and neutralising antibody) responses disproportionate to their replication. CpG-high infected mice also showed markedly reduced clinical severity, minimal weight loss and reduced immmunopathology in lung, yet sterilising immunity to lethal dose WT challenge was achieved after low dose (20PFU) pre-immunisation with this mutant. Increasing CpG dinucleotide frequencies represents a generic and potentially highly effective method for generating safe, highly immunoreactive vaccines. DOI: http://dx.doi.org/10.7554/eLife.12735.001