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VP2 of Infectious Bursal Disease Virus Induces Apoptosis via Triggering Oral Cancer Overexpressed 1 (ORAOV1) Protein Degradation.

ABSTRACT: Infectious bursal disease (IBD) is an acute, highly contagious and immunosuppressive avian disease caused by IBD virus (IBDV). Cell apoptosis triggered by IBDV contributes to the dysfunction of immune system in host. VP2 of IBDV is known to induce cell death but the underlying mechanism remains unclear. Here we demonstrate that VP2 interacts with the oral cancer overexpressed 1 (ORAOV1), a potential oncoprotein. Infection by IBDV or ectopic expression of VP2 causes a reduction of cellular ORAOV1 and induction of apoptosis, so does knockdown of ORAOV1. In contrast, over-expression of ORAOV1 leads to the inhibition of VP2- or IBDV-induced apoptosis, accompanied with the decreased viral release (p < 0.05). Thus, VP2-induced apoptosis during IBDV infection is mediated by interacting with and reducing ORAOV1, a protein that appears to act as an antiapoptotic molecule and restricts viral release early during IBDV infection.

SUBMITTER: Qin Y

PROVIDER: S-EPMC5515827 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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VP2 of Infectious Bursal Disease Virus Induces Apoptosis via Triggering Oral Cancer Overexpressed 1 (ORAOV1) Protein Degradation.

Qin Yao Y Xu Zhichao Z Wang Yongqiang Y Li Xiaoqi X Cao Hong H Zheng Shijun J SJ

Frontiers in microbiology 20170719

Infectious bursal disease (IBD) is an acute, highly contagious and immunosuppressive avian disease caused by IBD virus (IBDV). Cell apoptosis triggered by IBDV contributes to the dysfunction of immune system in host. VP2 of IBDV is known to induce cell death but the underlying mechanism remains unclear. Here we demonstrate that VP2 interacts with the oral cancer overexpressed 1 (ORAOV1), a potential oncoprotein. Infection by IBDV or ectopic expression of VP2 causes a reduction of cellular ORAOV1 ...[more]

PMID: 28769911

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Project description:Infectious bursal disease virus (IBDV) causes economically important immunosuppressive disease in young chickens. The self-assembling capsid protein (VP2) from IBDV strain IR01 was expressed in Pichia pastoris resulting in the formation of homomeric, 23-nm infectious bursal disease subviral particles (IBD-SVPs) with a yield of 76 mg/l before and 38 mg/l after purification. Anti-IBDV antibodies were detected in chickens injected with purified IBD-SVPs or fed with either purified IBD-SVPs or inactivated P. pastoris cells containing IBD-VP2 (cell-encapsulated). Challenge studies using the heterologous classical IBDV strain (MB3) showed that intramuscular vaccination with 20 µg purified IBD-SVPs conferred full protection, achieved complete virus clearance and prevented bursal damage and atrophy, compared with only 40% protection, 0-10% virus clearance accompanied by severe atrophy and substantial bursal damage in mock-vaccinated and challenge controls. The commercial IBDV vaccine also conferred full protection and achieved complete virus clearance, albeit with partial bursal atrophy. Oral administration of 500 µg purified IBD-SVPs with and without adjuvant conferred 100% protection but achieved only 60% virus clearance with adjuvant and none without it. Moderate bursal damage was observed in both cases but the inclusion of adjuvant resulted in bursal atrophy similar to that observed with live-attenuated vaccine and parenteral administration of 20 µg purified IBD-SVPs. The oral administration of 250 mg P. pastoris cells containing IBD-VP2 resulted in 100% protection with adjuvant and 60% without, accompanied by moderate bursal damage and atrophy in both groups, whereas 25 mg P. pastoris cells containing IBD-VP2 resulted in 90-100% protection with moderate bursal lesions and severe atrophy. Finally, the oral delivery of 50 µg purified IBD-SVPs achieved 40-60% protection with severe bursal lesions and atrophy. Both oral and parenteral administration of yeast-derived IBD-VP2 can therefore induce a specific and protective immune response against IBDV without affecting the growth rate of chickens.

Project description:BackgroundMedulloblastoma is the most common malignant brain tumor of childhood. Children who relapse usually die of their disease, which reflects resistance to radiation and/or chemotherapy. Improvements in outcome require a better understanding of the molecular basis of medulloblastoma growth and treatment response. TP73 is a member of the TP53 tumor suppressor gene family that has been found to be overexpressed in a variety of tumors and mediates apoptotic responses to genotoxic stress. In this study, we assessed expression of TP73 RNA species in patient tumor specimens and in medulloblastoma cell lines, and manipulated expression of full-length TAp73 and amino-terminal truncated DeltaNp73 to assess their effects on growth.MethodsWe analyzed medulloblastoma samples from thirty-four pediatric patients and the established medulloblastoma cell lines, Daoy and D283MED, for expression of TP73 RNA including the full-length transcript and the 5'-terminal variants that encode the DeltaNp73 isoform, as well as TP53 RNA using quantitative real time-RTPCR. Protein expression of TAp73 and DeltaNp73 was quantitated with immunoblotting methods. Clinical outcome was analyzed based on TP73 RNA and p53 protein expression. To determine effects of overexpression or knock-down of TAp73 and DeltaNp73 on cell cycle and apoptosis, we analyzed transiently transfected medulloblastoma cell lines with flow cytometric and TUNEL methods.ResultsPatient medulloblastoma samples and cell lines expressed full-length and 5'-terminal variant TP73 RNA species in 100-fold excess compared to non-neoplastic brain controls. Western immunoblot analysis confirmed their elevated levels of TAp73 and amino-terminal truncated DeltaNp73 proteins. Kaplan-Meier analysis revealed trends toward favorable overall and progression-free survival of patients whose tumors display TAp73 RNA overexpression. Overexpression of TAp73 or DeltaNp73 induced apoptosis under basal growth conditions in vitro and sensitized them to cell death in response to chemotherapeutic agents.ConclusionThese results indicate that primary medulloblastomas express significant levels of TP73 isoforms, and suggest that they can modulate the survival and genotoxic responsiveness of medulloblastomas cells.

Project description:BACKGROUND:Infectious bursal disease (IBD) is an acute contagious immunosuppressive disease which lead to acute bursal injury and immune dysfunction in poultry. It has caused heavy economic losses in the commercial poultry industry for many years in worldwide. Attenuated live vaccine has widely used in poultry showing some promising signs against IBDV infection. But it has defects such as generating enhanced virulence and immunosuppression prohibits. Therefore, the development of mucosal vaccines using the food-grade lactic acid bacterium is necessary. Here, we construct a recombinant Lactococcus co-expressing the major IBDV antigens VP2 and RCK protein of Salmonella enterica to prevent IBD. RESULTS:The recombinant fusion protein VP2-RCK was expressed in a soluble and stable form in the cytoplasm of the recombinant Lactococcus lactis. Animal experiments showed that: (1) the survival rates of the injected immunization inactivated recombinant LAB group and oral immunization live recombinant LAB group were 100% and 80%, respectively; (2) ELISA titers of all serum samples from all experimental groups were negative, but high amounts of specific neutralizing antibodies were detected (1:210 to 1:212); and (3) the bursas of the injected immunization inactivated recombinant LAB group did not suffer damage, as confirmed by clinical observation and bursal histopathological examination. Our results indicate that r-L. lactis-OptiVP2-RCK induces a specific neutralizing-antibody-mediated immune response that confers full protection against very-virulent IBDV (vvIBDV) challenge. CONCLUSION:Lactococcus lactis NZ3900 strain and its matching plasmid pNZ8149 could express the recombinant fusion protein VP2-RCK in a soluble form in the cytoplasm. The protective efficacy of r-L. lactis-OptiVP2-RCK (100%) was better than r-L. lactis-OptiVP2 (0%) which prove RCK protein played its unique role. The neutralizing antibodies titers against infectious bursal disease virus via one-time vaccination with inactivated r-L. lactis-OptiVP2-RCK could reach 1:210 to 1:212, but ELISA titers of all serum samples were negative. For this phenomenon, perhaps because of the change of delivery pathway or the spatial structure of fusion protein. We need further study to test these hypotheses.

Dataset Information

VP2 of Infectious Bursal Disease Virus Induces Apoptosis via Triggering Oral Cancer Overexpressed 1 (ORAOV1) Protein Degradation.

Publications

VP2 of Infectious Bursal Disease Virus Induces Apoptosis via Triggering Oral Cancer Overexpressed 1 (ORAOV1) Protein Degradation.

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