Abstract
BackgroundMany details in cell culture-derived influenza vaccine production are still poorly understood and approaches for process optimization mainly remain empirical. More insights on mammalian cell metabolism after a viral infection could give hints on limitations and cell-specific virus production capacities. A detailed metabolic characterization of an influenza infected adherent cell line (MDCK) was carried out based on extracellular and intracellular measurements of metabolite concentrations.ResultsFor most metabolites the comparison of infected (human influenza A/PR/8/34) and mock-infected cells showed a very similar behavior during the first 10-12 h post infection (pi). Significant changes were observed after about 12 h pi: (1) uptake of extracellular glucose and lactate release into the cell culture supernatant were clearly increased in infected cells compared to mock-infected cells. At the same time (12 h pi) intracellular metabolite concentrations of the upper part of glycolysis were significantly increased. On the contrary, nucleoside triphosphate concentrations of infected cells dropped clearly after 12 h pi. This behaviour was observed for two different human influenza A/PR/8/34 strains at slightly different time points.ConclusionsComparing these results with literature values for the time course of infection with same influenza strains, underline the hypothesis that influenza infection only represents a minor additional burden for host cell metabolism. The metabolic changes observed after12 h pi are most probably caused by the onset of apoptosis in infected cells. The comparison of experimental data from two variants of the A/PR/8/34 virus strain (RKI versus NIBSC) with different productivities and infection dynamics showed comparable metabolic patterns but a clearly different timely behavior. Thus, infection dynamics are obviously reflected in host cell metabolism.
Highlights
Many details in cell culture-derived influenza vaccine production are still poorly understood and approaches for process optimization mainly remain empirical
We focus on the analysis of the time course of a small number of important metabolites from central metabolism, because they can be highly informative and allow a clear distinction between metabolically different states
We present the investigation of influences of influenza virus infection on host cell metabolism by a quantitative metabolic profiling approach
Summary
Many details in cell culture-derived influenza vaccine production are still poorly understood and approaches for process optimization mainly remain empirical. A detailed metabolic characterization of an influenza infected adherent cell line (MDCK) was carried out based on extracellular and intracellular measurements of metabolite concentrations. Various continuous cell lines capable of a virus replication to high titers are reported in literature [2,3]. Apparently independent from apoptosis, central metabolism can be strongly affected by virus infections. A summary of early studies on metabolism of virus-infected animal cells is given by Koppelman & Evans [14]. A variety of other viruses have been shown to strongly influence host cell metabolism, e. A variety of other viruses have been shown to strongly influence host cell metabolism, e. g., rubella virus [19,20,21], cytomegalovirus [22,23,24], mayaro virus [25], dengue virus [26], mumps virus [27], newcastle-disease virus [27], polio virus [28,29,30] or reovirus [31]
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