A Novel Mechanism Underlying Antiviral Activity of an Influenza Virus M2-Specific Antibody
A Novel Mechanism Underlying Antiviral Activity of an Influenza Virus M2-Specific Antibody
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DOI：
10.1128/jvi.01277-20
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发表时间：
2021-01-01
影响因子：
5.4
通讯作者：
Takada，Ayato
中科院分区：
文献类型：
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作者：
Manzoor，Rashid;Eguchi，Nao;Takada，Ayato
针对甲型流感病毒（IAV）的保护性免疫通常取决于主要包膜糖蛋白血凝素（HA）的抗体，其抗原性在IAV亚型中是独特的。另一方面，基质2（M2）蛋白在抗原性上高度保守，并且已被研究为具有吸引力的疫苗抗原，以赋予针对多种亚型IAV的交叉保护性免疫。然而，M2特异性抗体的抗病毒机制尚未完全了解。在这里，我们报告的M2特异性单克隆抗体（MAb），rM 2ss 23的抗病毒活性的分子基础。我们首先发现rM 2ss 23抑制A/Aichi/2/1968（H3 N2）（Aichi）但不抑制A/PR/8/1934（H1N1）（PR 8）复制。rM 2ss 23可能通过交联分子改变了M2的细胞表面分布，并干扰了HA和M2的共定位，导致子代病毒出芽减少。然而，尽管rM 2 β 23与PR 8 M2具有结合能力，但对于另一种菌株PR 8未观察到这些效应。有趣的是，HA也参与PR 8对rM 2ss 23的抗性。我们还发现M2胞质尾区54和57位的两个氨基酸残基对于PR 8对rM 2ss 2的不敏感性至关重要。这些发现表明，M2-HA在感染细胞上共定位的破坏和随后病毒出芽的减少是M2特异性抗体的抗病毒活性的主要机制之一，并且抗M2抗体敏感的和抗M2抗体抗性的IAV在M2和HA之间的相互作用中具有不同的性质。大多数抗体是HA亚型特异性的，限制了基于HA的疫苗的潜力。相反，IAV M2蛋白已被研究为疫苗抗原以赋予针对具有多种HA亚型的IAV的交叉保护性免疫，因为M2是抗原保守的。尽管许多研究强调了抗HA中和和非中和抗体的保护作用，但关于M2特异性抗体作用的分子机制的精确信息仍不清楚。在这项研究中，我们发现，抗M2抗体干扰HA-M2协会，这是重要的有效出芽的后代病毒颗粒从感染的细胞。尽管抗体与M2的结合能力相似，但抗病毒活性是IAV毒株依赖性的，有趣的是，HA参与了对抗体的易感性。我们的数据提供了一种新的机制，M2特异性抗体的抗病毒活性。
Protective immunity against influenza A viruses (IAVs) generally depends on antibodies to the major envelope glycoprotein, hemagglutinin (HA), whose antigenicity is distinctive among IAV subtypes. On the other hand, the matrix 2 (M2) protein is antigenically highly conserved and has been studied as an attractive vaccine antigen to confer cross-protective immunity against multiple subtypes of IAVs. However, antiviral mechanisms of M2-specific antibodies are not fully understood. Here, we report the molecular basis of antiviral activity of an M2-specific monoclonal antibody (MAb), rM2ss23. We first found that rM2ss23 inhibited A/Aichi/2/1968 (H3N2) (Aichi) but not A/PR/8/1934 (H1N1) (PR8) replication. rM2ss23 altered the cell surface distribution of M2, likely by cross-linking the molecules, and interfered with the colocalization of HA and M2, resulting in reduced budding of progeny viruses. However, these effects were not observed for another strain, PR8, despite the binding capacity of rM2ss23 to PR8 M2. Interestingly, HA was also involved in the resistance of PR8 to rM2ss23. We also found that two amino acid residues at positions 54 and 57 in the M2 cytoplasmic tail were critical for the insensitivity of PR8 to rM2ss2. These findings suggest that the disruption of the M2-HA colocalization on infected cells and subsequent reduction of virus budding is one of the principal mechanisms of antiviral activity of M2-specific antibodies and that anti-M2 antibody-sensitive and -resistant IAVs have different properties in the interaction between M2 and HA.IMPORTANCEAlthough the IAV HA is the major target of neutralizing antibodies, most of the antibodies are HA subtype specific, restricting the potential of HA-based vaccines. On the contrary, the IAV M2 protein has been studied as a vaccine antigen to confer cross-protective immunity against IAVs with multiple HA subtypes, since M2 is antigenically conserved. Although a number of studies highlight the protective role of anti-HA neutralizing and nonneutralizing antibodies, precise information on the molecular mechanism of action of M2-specific antibodies is still obscure. In this study, we found that an anti-M2 antibody interfered with the HA-M2 association, which is important for efficient budding of progeny virus particles from infected cells. The antiviral activity was IAV strain dependent despite the similar binding capacity of the antibody to M2, and, interestingly, HA was involved in susceptibility to the antibody. Our data provide a novel mechanism underlying antiviral activity of M2-specific antibodies.