Marek's Disease Viral Interleukin-8 Promotes Lymphoma Formation through Targeted Recruitment of B Cells and CD4+ CD25+ T Cells
Marek's Disease Viral Interleukin-8 Promotes Lymphoma Formation through Targeted Recruitment of B Cells and CD4+ CD25+ T Cells
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DOI：
10.1128/jvi.00556-12
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发表时间：
2012-08-01
影响因子：
5.4
通讯作者：
Kaufer, Benedikt B.
中科院分区：
文献类型：
--
作者：
Engel, Annemarie T.;Selvaraj, Ramesh K.;Kaufer, Benedikt B.
马立克氏病病毒（MDV）是一种感染鸡的细胞相关和高度致癌的α疱疹病毒。在裂解性和潜伏性MDV感染期间，表达称为病毒白细胞介素-8（vIL-8）的CXC趋化因子。整个vIL-8开放阅读框（ORF）的缺失显示严重损害疾病进展和肿瘤发展;然而，尚不清楚这种表型是由于分泌的vIL-8的丢失还是由于将vIL-8的外显子II和III融合到某些上游开放阅读框（包括病毒癌蛋白Meq）的剪接变体的丢失。为了特异性地检测分泌的vIL-8在MDV发病机制中的作用，我们构建了重组病毒v Delta MetvIL-8，其中我们从编码外显子I的信号肽中删除了天然起始密码子。该突变体缺乏分泌型vIL-8，但不影响Meq vIL-8剪接变体。分泌的vIL-8的丧失导致通过腹腔内途径感染v Delta MetvIL-8的动物中疾病和肿瘤发病率高度降低。尽管v Delta MetvIL-8仍然能够通过自然途径传播到未处理动物，但接触动物中的感染和淋巴瘤发生严重受损。体外试验表明，纯化的重组vIL-8有效地结合并诱导B细胞的趋化性，B细胞是裂解性MDV复制的主要靶标，并且还与MDV转化的已知靶标CD 4（+）CD 25（+）T细胞相互作用。我们的数据提供了vIL-8吸引B和CD 4（+）CD 254（+）T细胞以募集裂解和潜伏感染的靶的证据。
Marek's disease virus (MDV) is a cell-associated and highly oncogenic alphaherpesvirus that infects chickens. During lytic and latent MDV infection, a CXC chemokine termed viral interleukin-8 (vIL-8) is expressed. Deletion of the entire vIL-8 open reading frame (ORF) was shown to severely impair disease progression and tumor development; however, it was unclear whether this phenotype was due to loss of secreted vIL-8 or of splice variants that fuse exons II and III of vIL-8 to certain upstream open reading frames, including the viral oncoprotein Meq. To specifically examine the role of secreted vIL-8 in MDV pathogenesis, we constructed a recombinant virus, v Delta MetvIL-8, in which we deleted the native start codon from the signal peptide encoding exon I. This mutant lacked secreted vIL-8 but did not affect Meq vIL-8 splice variants. Loss of secreted vIL-8 resulted in highly reduced disease and tumor incidence in animals infected with v Delta MetvIL-8 by the intra-abdominal route. Although v Delta MetvIL-8 was still able to spread to naive animals by the natural route, infection and lymphomagenesis in contact animals were severely impaired. In vitro assays showed that purified recombinant vIL-8 efficiently binds to and induces chemotaxis of B cells, which are the main target for lytic MDV replication, and also interacts with CD4(+) CD25(+) T cells, known targets of MDV transformation. Our data provide evidence that vIL-8 attracts B and CD4(+) CD254(+) T cells to recruit targets for both lytic and latent infection.