Induction of epitope-specific neutralizing antibodies against west nile virus
Induction of epitope-specific neutralizing antibodies against west nile virus
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DOI：
10.1128/jvi.00643-07
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发表时间：
2007-11-01
影响因子：
5.4
通讯作者：
Diamond, Michael S.
中科院分区：
文献类型：
--
作者：
Oliphant, Theodore;Nybakken, Grant E.;Diamond, Michael S.
先前的研究已经确定，西尼罗病毒（WNV）包膜（E）蛋白的结构域III（DIII-lr）的侧脊上的表位被强中和型特异性抗体识别。相反，针对结构域II中的融合环（DII-fl）的表位被具有较低中和潜力的黄病毒交叉反应性抗体识别。使用获得和丧失功能的E蛋白和野生型和变体WNV报告病毒颗粒，我们评估了WNV感染后小鼠和人血清中针对DIII-lr和DII-fl表位的抗体的表达模式和活性。在小鼠中，在感染后第6天检测到低水平的针对DIIII-Ir表位的免疫球蛋白M（IgM）抗体。然而，与在第8天容易检测到的针对DI和DII中的其他表位的IgG应答相比，针对DIII-Ir表位的IgG的发展被延迟，并且直到第15天才一致地出现。这个较晚的时间点是值得注意的，因为小鼠中VVNV感染后几乎所有的死亡都发生在第12天。尽管如此，在后来的时间点，DIII-lr抗体积累并构成了DIII特异性IgG反应的很大一部分。在感染者的血清中，检测到低水平的DIII-lr抗体，与临床结果无关。相比之下，在所有人血清样品中检测到针对DII-fl的抗体，并且包括显著百分比的抗E蛋白应答。我们的实验表明，高度中和的DIII-lr IgG抗体在原发性感染中几乎没有显著作用，并且人的抗体应答可能偏向于诱导交叉反应性的、中和性较低的抗体。
Previous studies have established that an epitope on the lateral ridge of domain III (DIII-lr) of West Nile virus (WNV) envelope (E) protein is recognized by strongly neutralizing type-specific antibodies. In contrast, an epitope against the fusion loop in domain II (DII-fl) is recognized by flavivirus cross-reactive antibodies with less neutralizing potential. Using gain- and loss-of-function E proteins and wild-type and variant WNV reporter virus particles, we evaluated the expression pattern and activity of antibodies against the DIII-lr and DII-fl epitopes in mouse and human serum after WNV infection. In mice, immunoglobulin M (IgM) antibodies to the DIII-Ir epitope were detected at low levels at day 6 after infection. However, compared to IgG responses against other epitopes in DI and DII, which were readily detected at day 8, the development of IgG against DIII-lr epitope was delayed and did not appear consistently until day 15. This late time point is notable since almost all death after VVNV infection in mice occurs by day 12. Nonetheless, at later time points, DIII-lr antibodies accumulated and comprised a significant fraction of the DIII-specific IgG response. In sera from infected humans, DIII-lr antibodies were detected at low levels and did not correlate with clinical outcome. In contrast, antibodies to the DII-fl were detected in all human serum samples and encompassed a significant percentage of the anti-E protein response. Our experiments suggest that the highly neutralizing DIII-lr IgG antibodies have little significant role in primary infection and that the antibody response of humans may be skewed toward the induction of cross-reactive, less-neutralizing antibodies.