Plant Ewan P, Ilyushina Natalia A, Sheikh Faruk, Donnelly Raymond P, Ye Zhiping
Division of Viral Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, USA.
Division of Biotechnology Research and Review II, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, USA.
Virus Res. 2017 Aug 15;240:81-86. doi: 10.1016/j.virusres.2017.07.021. Epub 2017 Jul 27.
The influenza virus NS1 protein interacts with a wide range of proteins to suppress the host cell immune response and facilitate virus replication. The amino acid sequence of the 2009 pandemic virus NS1 protein differed from sequences of earlier related viruses. The functional impact of these differences has not been fully defined. Therefore, we made mutations to the NS1 protein based on these sequence differences, and assessed the impact of these changes on host cell interferon (IFN) responses. We found that viruses with mutations at position 171 replicated efficiently but did not induce expression of interferon genes as effectively as wild-type viruses in A459 lung epithelial cells. The decreased ability of these NS1 mutant viruses to induce IFN gene and protein expression correlated with decreased activation of STAT1 and lower levels of IFN-stimulated gene (ISG) expression. These findings demonstrate that mutations at position 171 in the NS1 protein result in decreased expression of IFN and ISGs by A549 cells. Consequently, these viruses may be more virulent than the parental strains that do not contain mutations at position 171 in the NS1 protein.
流感病毒NS1蛋白与多种蛋白相互作用，以抑制宿主细胞免疫反应并促进病毒复制。2009年大流行病毒NS1蛋白的氨基酸序列与早期相关病毒的序列不同。这些差异的功能影响尚未完全明确。因此，我们基于这些序列差异对NS1蛋白进行了突变，并评估了这些变化对宿主细胞干扰素（IFN）反应的影响。我们发现，在A459肺上皮细胞中，171位发生突变的病毒能够高效复制，但诱导干扰素基因表达的效果不如野生型病毒。这些NS1突变病毒诱导IFN基因和蛋白表达的能力下降，与STAT1激活减少以及干扰素刺激基因（ISG）表达水平降低相关。这些发现表明，NS1蛋白171位的突变导致A549细胞中IFN和ISG表达减少。因此，这些病毒可能比NS1蛋白171位未发生突变的亲本毒株更具毒性。
