Pleiotropic regulatory function of the lysr family transcriptional regulator cpsy during streptococcus iniae systemic infection

The ability of a pathogen to metabolically adapt to the local environment for optimal expression of virulence determinants is a continued area of research. Orthologs of the Streptococcus iniae LysR family regulator CpsY have been shown to regulate methionine biosynthesis and uptake pathways, but appear to influence expression of several virulence genes as well. A S. iniae mutant with an in-frame deletion of cpsY (cpsY) is highly attenuated in a zebrafish infection model. The cpsY mutant displays a methionine-independent growth defect in serum, which differs from the methionine-dependent defect observed for orthologous mutants of S. mutans and S. agalactiae. On the contrary, the cpsY mutant can grow in excess of WT when supplemented with proteose peptone, suggesting an inability to properly regulate growth. CpsY is critical for protection of S. iniae from clearance by neutrophils in whole blood, but is dispensable for intracellular survival in macrophages. Susceptibility of the cpsY mutant to killing in whole blood is not due to a growth defect because inhibition of neutrophil phagocytosis rescues the mutant to WT levels. Thus CpsY appears to have a pleiotropic regulatory role for S. iniae, integrating metabolism and virulence. Furthermore S. iniae provides a unique model to investigate the paradigm of CpsY-dependent regulation during systemic streptococcal infection. 2