Marek's disease viral interleukin-8 promotes lymphoma formation through targeted recruitment of B cells and CD4+ CD25+ T cells.
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, vΔMetvIL-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 vΔMetvIL-8 by the intra-abdominal route. Although vΔMetvIL-8 was still able to spread to naïve 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(+) CD25(+) T cells to recruit targets for both lytic and latent infection.
Institut für Virologie, Freie Universität Berlin, Berlin, Germany.
Annemarie T
AT
Engel
Ramesh K
RK
Selvaraj
Jeremy P
JP
Kamil
Nikolaus
N
Osterrieder
Benedikt B
BB
Kaufer
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000502:physiology*; D002633:Chemotaxis; D002645:Chickens; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008223:Lymphoma / Q000473:pathology* / Q000821:virology; D025922:Mardivirus / Q000472:pathogenicity*; D008380:Marek Disease / Q000276:immunology / Q000473:pathology / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D021382:Protein Sorting Signals / Q000235:genetics; D017384:Sequence Deletion; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
D053645:Interleukin-2 Receptor alpha Subunit; D009856:Oncogene Proteins, Viral; D021382:Protein Sorting Signals; D037521:Virulence Factors; C559372:vIL-8 protein, Marek's disease virus