Heterosubtypic antiviral activity of hemagglutinin-specific antibodies induced by intranasal immunization with inactivated influenza viruses in mice.
Heterosubtypic antiviral activity of hemagglutinin-specific antibodies induced by intranasal immunization with inactivated influenza viruses in mice.
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DOI：
10.1371/journal.pone.0071534
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Takada A
中科院分区：
文献类型：
--
作者：
Muramatsu M;Yoshida R;Miyamoto H;Tomabechi D;Kajihara M;Maruyama J;Kimura T;Manzoor R;Ito K;Takada A
甲型流感病毒亚型根据其包膜糖蛋白、血凝素（HA; H1-H17）和神经氨酸酶的抗原性进行分类。由于HA特异性中和抗体主要对单一HA亚型具有特异性，因此抗体对异亚型免疫的贡献尚未完全了解。在本研究中，用具有H1、H3、H5、H7、H9或H13 HA亚型的病毒鼻内或皮下免疫小鼠，并分析诱导的IgG和伊加抗体与H1-H16亚型的重组HA的交叉反应性。我们发现皮下和鼻内免疫均诱导了对多种不同亚型HA的抗体应答，而皮下免疫小鼠未检测到明显的伊加。使用H9病毒免疫小鼠的血清、鼻洗液和气管-肺洗液样品，然后通过空斑减少测定来评估交叉反应性抗体的中和活性。正如预期，通过标准中和试验未检测到异亚型中和活性，其中在接种到培养细胞中之前将病毒与抗体混合。然而，有趣的是，当感染的细胞随后与含有HA特异性交叉反应性IgA的样品一起培养时，观察到噬斑形成和H12病毒的细胞外释放显著减少，所述H12病毒被H9诱导的交叉反应性抗体结合。当样品用抗小鼠伊加多克隆血清预处理时，这种异亚型斑块减少受到干扰。这些结果表明，大多数HA特异性的交叉反应性IgG和伊加抗体产生的免疫接种不阻断病毒的细胞进入，但交叉反应性伊加可能有可能抑制病毒从感染的细胞中流出，从而发挥作用，在异亚型免疫对甲型流感病毒。
Influenza A virus subtypes are classified on the basis of the antigenicity of their envelope glycoproteins, hemagglutinin (HA; H1–H17) and neuraminidase. Since HA-specific neutralizing antibodies are predominantly specific for a single HA subtype, the contribution of antibodies to the heterosubtypic immunity is not fully understood. In this study, mice were immunized intranasally or subcutaneously with viruses having the H1, H3, H5, H7, H9, or H13 HA subtype, and cross-reactivities of induced IgG and IgA antibodies to recombinant HAs of the H1–H16 subtypes were analyzed. We found that both subcutaneous and intranasal immunizations induced antibody responses to multiple HAs of different subtypes, whereas IgA was not detected remarkably in mice immunized subcutaneously. Using serum, nasal wash, and trachea-lung wash samples of H9 virus-immunized mice, neutralizing activities of cross-reactive antibodies were then evaluated by plaque-reduction assays. As expected, no heterosubtypic neutralizing activity was detected by a standard neutralization test in which viruses were mixed with antibodies prior to inoculation into cultured cells. Interestingly, however, a remarkable reduction of plaque formation and extracellular release of the H12 virus, which was bound by the H9-induced cross-reactive antibodies, was observed when infected cells were subsequently cultured with the samples containing HA-specific cross-reactive IgA. This heterosubtypic plaque reduction was interfered when the samples were pretreated with anti-mouse IgA polyclonal serum. These results suggest that the majority of HA-specific cross-reactive IgG and IgA antibodies produced by immunization do not block cellular entry of viruses, but cross-reactive IgA may have the potential to inhibit viral egress from infected cells and thus to play a role in heterosubtypic immunity against influenza A viruses.
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