Abstract
Phages can reshape the metabolic network of hosts to support specific requirements for replication during infection. However, metabolomic profiling of phage-elicited host global metabolic alterations and the linkage of phage-encoded auxiliary metabolic genes to these alterations are understudied. In this study, the dynamics of intracellular metabolites of Dinoroseobacter shibae DFL12, a member of marine environmentally and biogeochemically relevant Roseobacter clade, in response to four distinct lytic roseophage infections were investigated. Metabolomic profiling indicated that roseophage infections significantly altered host metabolism in a phage-specific manner. Pathway enrichment analyses showed that the central carbon pathway and DNA, amino acid, and coenzyme metabolism were commonly altered by roseophages, revealing a central role of these pathways in phage replication. Furthermore, clear infection stage-specific host responses were observed, corresponding to different metabolic demands of phage replication in the early and late infection stages. Interestingly, the content of host vitamin B(1), which is the essential nutrient provided by D. shibae to its symbiotic microalgae, increased in the early infection stage for most roseophages, implying that phage infection may impact the symbiosis of D. shibae with microalgae. Finally, combined metabolomic and phage genomics analyses showed that roseophages adopt different strategies to expand the host pyrimidine pool (recycling or de novo synthesis of pyrimidine nucleotides), and this difference was likely related to variation in the GC content between phage and host genomes. Collectively, these results highlight the potential importance of phage-specific and infection stage-specific host metabolic reprogramming in marine phage-host interactions, bacteria-microalgae symbiosis, and biogeochemical cycles.