Dysregulation of M segment gene expression contributes to influenza A virus host restriction
Dysregulation of M segment gene expression contributes to influenza A virus host restriction
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DOI：
10.1371/journal.ppat.1007892
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发表时间：
2019-08-01
期刊：
影响因子：
6.7
通讯作者：
Steel, John
中科院分区：
文献类型：
--
作者：
Calderon, Brenda M.;Danzy, Shamika;Steel, John
2009年大流行性甲型流感病毒（IAV）的M片段与其出现在人群中有关。为了阐明M片段对宿主适应的遗传贡献及其潜在机制，我们检测了一组携带禽源或人源M片段的同基因病毒。在哺乳动物模型系统中，禽类（而非人类）的M片段限制了病毒的生长和传播，并且这种受限制的生长与M2相对于M1的表达增加相关。M2的过度表达与细胞内自噬体的积累有关，这是通过金刚烷胺治疗干扰病毒质子通道活性而减轻的。由于M1和M2通过选择性剪接从M mRNA表达，我们分离了区分人类和禽类M片段的同义和非同义变化，并发现导致M2过表达的基因表达失调减少了复制，而与M1或M2的氨基酸组成无关。此外，尽管有效的复制，病毒具有一个人的M节段，在低水平表达禽M2蛋白没有有效地传播。我们的结论是，（i）决定因素的传输驻留在IAV M2蛋白，和（ii）控制M段基因的表达是一个关键方面的IAV宿主适应需要防止M2介导的囊泡稳态失调。
The M segment of the 2009 pandemic influenza A virus (IAV) has been implicated in its emergence into human populations. To elucidate the genetic contributions of the M segment to host adaptation, and the underlying mechanisms, we examined a panel of isogenic viruses that carry avian-or human-derived M segments. Avian, but not human, M segments restricted viral growth and transmission in mammalian model systems, and the restricted growth correlated with increased expression of M2 relative to M1. M2 overexpression was associated with intracellular accumulation of autophagosomes, which was alleviated by interference of the viral proton channel activity by amantadine treatment. As M1 and M2 are expressed from the M mRNA through alternative splicing, we separated synonymous and non-synonymous changes that differentiate human and avian M segments and found that dysregulation of gene expression leading to M2 overexpression diminished replication, irrespective of amino acid composition of M1 or M2. Moreover, in spite of efficient replication, virus possessing a human M segment that expressed avian M2 protein at low level did not transmit efficiently. We conclude that (i) determinants of transmission reside in the IAV M2 protein, and that (ii) control of M segment gene expression is a critical aspect of IAV host adaptation needed to prevent M2-mediated dysregulation of vesicular homeostasis.