Marek's disease virus-encoded vIL-8 gene is involved in early cytolytic infection but dispensable for establishment of latency
Marek's disease virus-encoded vIL-8 gene is involved in early cytolytic infection but dispensable for establishment of latency
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DOI：
10.1128/jvi.78.9.4753-4760.2004
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发表时间：
2004-05-01
影响因子：
5.4
通讯作者：
Reddy, SM
中科院分区：
文献类型：
--
作者：
Cui, XP;Lee, LF;Reddy, SM
马立克氏病是一种鸡的淋巴组织增生性疾病，由α疱疹病毒马立克氏病病毒（MDV）引起。该病毒编码病毒因子vIL-8，与细胞CXC趋化因子如白细胞介素-8（IL-8）和Gro-α具有一般同源性。为了研究vIL-8基因的功能，我们删除了位于病毒基因组的末端重复序列长区和内部重复序列长区的vIL-8的两个拷贝，并产生了vIL-8缺失的突变病毒，rMd 5/DeltavIL-8。生长动力学研究表明，vIL-8基因在细胞培养中对病毒复制是不利的。在体内，vIL-8基因参与淋巴器官中的早期溶细胞感染，如rMd 5/DeltavIL-8的有限病毒抗原表达所证明。然而，rMd 5/DeltavIL-8病毒在羽囊上皮中的病毒复制未受损。vIL-8似乎对潜伏期的建立并不重要，因为rMd 5/DeltavIL-8和野生型病毒在感染后14天具有相似的病毒血症滴度，在此期间病毒滴度主要来自重新激活的潜伏基因组。然而，由于受损的溶细胞感染，vIL-8缺失的病毒的总体转化效率低得多，如接种后5周转化细胞数量减少和存在更少的大体肿瘤所反映的。重要的是，恢复vIL-8基因表达的回复突变病毒也恢复了野生型表型，表明缺陷表型是vIL-8缺失的结果。MDV vIL-8基因与其细胞对应物之间的有趣差异之一是在不变的CXC基序之前存在DKR（Asp-Lys-Arg）基序而不是ELR（Glu-Leu-Arg）。为了研究这种变异的意义，我们制备了携带ELR基序的重组MDV，rMd 5/vIL-8-ELR。体内外研究表明，DKR基序在MDV的致病机制中与ELR一样有效。
Marek's disease, a lymphoproliferative disease of chickens, is caused by an alphaherpesvirus, Marek's disease virus (MDV). This virus encodes a virokine, vIL-8, with general homology to cellular CXC chemokines such as interleukin-8 (IL-8) and Gro-alpha. To study the function of vIL-8 gene, we deleted both copies of vIL-8 residing in the terminal repeat long and internal repeat long region of the viral genome and generated a mutant virus with vIL-8 deleted, rMd5/DeltavIL-8. Growth kinetics study showed that vIL-8 gene is dispensable for virus replication in cell culture. In vivo, the vIL-8 gene is involved in early cytolytic infections in lymphoid organs, as evidenced by limited viral antigen expression of rMd5/DeltavIL-8. However, the rMd5/DeltavIL-8 virus is unimpaired in virus replication in the feather follicle epithelium. vIL-8 does not appear to be important for establishment of latency, since rMd5/DeltavIL-8 and the wild-type virus have similar viremia titers at 14 days postinfection, a period when the virus titer comes primarily from reactivated latent genomes. Nevertheless, because of the impaired cytolytic infections, the overall transformation efficiency of the virus with vIL-8 deleted is much lower, as reflected by the reduced number of transformed cells at 5 weeks postinoculation and the presence of fewer gross tumors. Importantly, the revertant virus that restored the expression of vIL-8 gene also restored the wild-type phenotype, indicating the deficient phenotypes are results of vIL-8 deletion. One of the interesting differences between the MDV vIL-8 gene and its cellular counterpart is the presence of a DKR (Asp-Lys-Arg) motif instead of ELR (Glu-Leu-Arg) preceding the invariable CXC motif. To study the significance of this variation, we generated recombinant MDV, rMd5/vIL-8-ELR, carrying the ELR motif. Both in vitro and in vivo studies revealed that the DKR motif is as competent as ELR in pathogenesis of MDV.