Effects of Ikaros (IKZF1) gene in the virulence of Marek's disease virus.

Abstract

Marek's disease (MD) caused by the oncogenic avian herpesvirus, Marek's disease virus (MDV) has significant economic impacts on the poultry industry because MDV is ubiquitous in the environment and most chickens are exposed to the threat by MDV from the first day of age. Meq, a bZIP transactivator, is required for tumor formation by MDV, mostly T cell lymphomas. Additionally, Ikaros (IKZF1) has been identified as a cancer driver gene for MDV tumorigenesis. The safety of G2M-WT-Ikaros, which contains wildtype IKZF1 gene in the virulent MDV genome as a potential vaccine candidate, was compared with the parental G2M and Rispens vaccine. Although G2M-WT-Ikaros has significantly reduced virulence (tumor formations), immunosuppression by the atrophies of thymus and bursa remained. The immune suppressions of G2M-Ikaros viruses with Meq, G2M-WT-Ikaros, G2M-MUT-Ikaros, or without Meq, G2M∆MeqWT-Ikaros, G2M∆MeqMUT-Ikaros were compared with G2M viruses. Interestingly, G2M-MUT-Ikaros showed the highest virulence in tumor formation, mortality, and MD incidences, even higher than that of parental G2M viruses, while G2M-WT-Ikaros showed reduced tumorigenicity and MD incidences. With Meq deletion, G2M∆MeqWT-Ikaros, and G2M∆MeqMUT-Ikaros virus significantly reduced tumor formations; however, the immunosuppression by those viruses still occurred, regardless of the different IKZF1 gene sequences, either wildtype or somatic mutated, in the MDV genome. Thus, MDV tumorigenicity by Meq gene is enhanced by IKZF1 mutations, but ectopic wildtype IKZF1 expression showed suppression of MDV-induced tumors.