Coupling metabolomics analysis and DOE optimization strategy towards enhanced IBDV production by chicken embryo fibroblast DF-1 cells.

Infectious bursal disease (IBD) caused by IBD virus (IBDV) is highly contagious viral and vaccination in chicken embryo has been an effective mean to prevent acute infection. However, the current production of IBDV vaccine faces serious batch instability and external contamination. The chicken embryonic fibroblast cell line DF-1 is widely used for the proliferation of avian viruses and vaccine production. Thus, optimizing the production of IBDV by DF-1 cells has an important application value. Combining metabolomics analysis and a Design of Experiments (DOE) statistical strategy, this study successfully optimized the process of IBDV production by DF-1 cells. Differential analysis and time series analysis of metabolite data in both IBDV-infected and uninfected DF-1 cells were performed by multivariate statistical analysis. The results showed that the intracellular metabolite intensities of glycolysis, the pentose phosphate pathway, the nucleoside synthesis pathway, lipid metabolism, and glutathione metabolism were upregulated, and the TCA cycle underwent a slight downregulation after IBDV infection of DF-1 cells. Based on the metabolome results and DOE statistical optimization method, the additive components suitable for IBDV proliferation were determined. The IBDV titer increased by 20.7 times upon exogenous addition of cysteine, methionine, lysine and nucleosides in the control medium, which is consistent with the predicted result (20.0 times) by a multivariate quadratic equation. This study provides a strategy for the efficient production of IBDV vaccines and could potentially be utilized to improve the production of other viral vaccines and biologics.