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Ovine Herpesvirus 2 Encodes a Previously Unrecognized Protein, pOv8.25, That Targets Mitochondria and Triggers Apoptotic Cell Death.
Journal of Virology ( IF 5.4 ) Pub Date : 2020-03-31 , DOI: 10.1128/jvi.01536-19
Neeta Shrestha 1 , Kurt Tobler 1 , Stephanie Uster 1 , Romina Sigrist-Nagy 1 , Melanie Michaela Hierweger 2, 3 , Mathias Ackermann 4
Affiliation  

Malignant catarrhal fever (MCF) is a rare but frequently lethal disease of certain cloven-hoofed animals. At least 10 different viruses, all members of the Macavirus genus in the subfamily Gammaherpesvirinae, are known as causative agents of MCF. Among these, ovine herpesvirus 2 (OvHV-2) is the most frequent and economically most important MCF agent. Phenotypically, MCF is characterized by severe lymphocytic arteritis-periarteritis, which leads to the accumulation of activated lymphocytes accompanied by apoptosis and necrosis in a broad range of tissues. However, a viral factor that might be responsible for tissue damage has not yet been identified. We have studied a seemingly intergenic locus on the OvHV-2 genome, which was previously shown to be transcriptionally highly active in MCF-affected tissue. We identified by 5' and 3' rapid amplification of cDNA ends (RACE) a conserved, double-spliced transcript that encoded a 9.9-kDa hydrophobic protein. The newly detected gene, Ov8.25, and its splicing pattern were conserved among OvHV-2 strains of different origins. Upon transient expression of synthetic variants of this gene in various cell types, including bovine lymphocytes, the protein (pOv8.25) was shown to target mitochondria, followed by caspase-dependent apoptosis and necrosis. Notably, a deletion mutant of the same protein lost these abilities. Finally, we detected pOv8.25 in brain-infiltrating lymphocytes of cattle with MCF. Thus, the cell death-causing properties of pOv8.25 in affected cells may be involved in the emergence of typical MCF-associated apoptosis and necrosis. Thus, we have identified a novel OvHV-2 protein, which might contribute to the phenotype of MCF-related lesions.IMPORTANCE Ovine herpesvirus 2 (OvHV-2) circulates among sheep without causing disease. However, upon transmission to cattle, the same virus instigates a frequently lethal disease, malignant catarrhal fever (MCF). While the cause of death and pathogenesis of tissue lesions are still poorly understood, MCF is characterized by the accumulation of lymphocytes in various tissues, associated with vasculitis and cell death. As infectious virus is hardly present in these lesions, the cause of cell death cannot be explained simply by viral replication. The significance of our research is in identifying and characterizing a previously overlooked gene of OvHV-2 (Ov8.25), which is highly expressed in animals with MCF. Its encoded protein targets mitochondria, causing apoptosis and necrosis, thus contributing to an understanding of the source and nature of cell death. As the corresponding genetic locus is also active in the context of MCF due to a different macavirus, we may have detected a common denominator of the disease phenotype.

中文翻译:

绵羊疱疹病毒2编码以前无法识别的蛋白质pOv8.25,该蛋白质靶向线粒体并触发凋亡性细胞死亡。

恶性卡他热(MCF)是某些偶蹄类动物罕见但致命的疾病。至少有10种不同的病毒,即Gammaherpesvirinae亚科的Macavirus属的所有成员,被称为MCF的病原体。其中,绵羊疱疹病毒2(OvHV-2)是最常见且经济上最重要的MCF药物。从表型上看,MCF的特征是严重的淋巴细胞性动脉炎-心包炎,导致活化的淋巴细胞积聚,并伴随着广泛组织的凋亡和坏死。但是,尚未发现可能导致组织损伤的病毒因子。我们研究了OvHV-2基因组上一个看似基因间的基因座,该基因座先前已证明在受MCF影响的组织中具有转录高度活性。我们用5'和3'标识 cDNA末端的快速扩增(RACE)是一种保守的双剪接转录本,可编码9.9 kDa疏水蛋白。新检测到的基因Ov8.25及其剪接模式在不同来源的OvHV-2菌株中均得到保留。该基因的合成变异体在各种细胞类型(包括牛淋巴细胞)中瞬时表达后,该蛋白(pOv8.25)被显示为靶向线粒体,随后是caspase依赖性凋亡和坏死。值得注意的是,相同蛋白质的缺失突变体失去了这些能力。最后,我们用MCF在牛的脑浸润淋巴细胞中检测到pOv8.25。因此,在受影响的细胞中pOv8.25的导致细胞死亡的特性可能与典型的MCF相关的细胞凋亡和坏死的出现有关。因此,我们确定了一种新的OvHV-2蛋白,重要提示绵羊疱疹病毒2(OvHV-2)在绵羊中循环而不会引起疾病。但是,一旦传播到牛,同一病毒会引发经常致命的疾病,即恶性卡他热(MCF)。尽管对死亡的原因和组织损伤的发病机理仍知之甚少,但MCF的特征是淋巴细胞在各种组织中的积累,与血管炎和细胞死亡有关。由于这些病变中几乎不存在传染性病毒,因此不能仅通过病毒复制来解释细胞死亡的原因。我们研究的意义在于鉴定和表征以前被忽视的OvHV-2(Ov8.25)基因,该基因在患有MCF的动物中高度表达。其编码的蛋白质靶向线粒体,导致细胞凋亡和坏死,因此有助于了解细胞死亡的来源和性质。由于不同的Macavirus,相应的遗传位点在MCF中也具有活性,因此我们可能已经检测到疾病表型的共同指标。
更新日期:2020-02-05
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