Bovine herpesvirus 1 (BHV-1) causes respiratory infection and abortion in cattle. Following a primary infection, BHV-1 establishes lifelong latency in the trigeminal ganglia (TG). Periodic reactivation of the latent virus in TG neurons results in anterograde virus transport to nerve endings in the nasal mucosa and nasal virus shedding. The BHV-1 glycoprotein E cytoplasmic tail (gE-CT) is necessary for virus cell-to-cell spread in epithelial cells and neuronal anterograde transport. Recently, we identified two tyrosine residues, Y467 and Y563, within the tyrosine-based motifs ₄₆₇YTSL₄₇₀ and ₅₆₃YTVV₅₆₆, which, together, account for the gE CT-mediated efficient cell-to-cell spread of BHV-1 in epithelial cells. Here, we determined that in primary neuron cultures in vitro, the individual alanine exchange Y467A or Y563A mutants had significantly diminished anterograde axonal spread. Remarkably, the double-alanine-exchanged Y467A/Y563A mutant virus was not transported anterogradely. Following intranasal infection of rabbits, both wild-type (wt) and the Y467A/Y563A mutant viruses established latency in the TG. Upon dexamethasone-induced reactivation, both wt and the mutant viruses reactivated and replicated equally efficiently in the TG. However, upon reactivation, only the wt, not the mutant, was isolated from nasal swabs. Therefore, the gE-CT tyrosine residues Y467 and Y563 together are required for gE CT-mediated anterograde neuronal transport.

中文翻译：

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牛疱疹病毒1的糖蛋白E细胞质尾内的两个基于酪氨酸的YXXL /Φ基序参与病毒顺行神经元转运。

牛疱疹病毒1（BHV-1）引起牛的呼吸道感染和流产。初次感染后，BHV-1在三叉神经节（TG）中建立了终身潜伏期。TG神经元中潜伏病毒的定期重新激活导致顺行病毒转运到鼻粘膜的神经末梢和鼻病毒脱落。BHV-1糖蛋白E胞质尾（gE-CT）对于病毒在上皮细胞中的细胞间传播和神经元顺行转运是必需的。最近，我们在基于酪氨酸的基序₄₆₇ YTSL ₄₇₀和₅₆₃ YTVV _566中鉴定了两个酪氨酸残基Y467和Y563，这一起解释了gE CT介导的BHV-1在上皮细胞中的有效细胞间传播。在这里，我们确定在体外原代神经元培养物中，单个丙氨酸交换Y467A或Y563A突变体已大大减少了顺行轴突的扩散。值得注意的是，双丙氨酸交换的Y467A / Y563A突变病毒并未顺地转运。鼻内感染兔子后，野生型（wt）和Y467A / Y563A突变病毒均在TG中建立了潜伏期。在地塞米松诱导的重新激活后，wt和突变型病毒均重新激活，并在TG中有效复制。然而，重新活化后，仅从鼻拭子中分离出wt而不是突变体。因此，gE CT介导的顺行神经元运输需要gE-CT酪氨酸残基Y467和Y563。