Open Access Dissertation
Date of Award
Immunology and Microbiology
Melody N. Neely
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 is highly attenuated in a zebrafish infection model. The cpsY deletion 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 deletion 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 deletion mutant to killing in whole blood is not due to a growth defect because inhibition of neutrophil phagocytosis rescues the mutant to WT levels. S. iniae does not alter neutrophil phagosomal maturation, but instead is able to adapt to the extreme bactericidal environment of a mature neutrophil phagosome dependent upon CpsY. This CpsY-dependent adaptation appears to involve stabilization of the cell wall in part through peptidoglycan O-acetylation and repression of cellular autolysins. In addition, CpsY may influence these processes by responding to nutritional stress. The ability of a pathogen to evade neutrophil phagocytic killing mechanisms is critically important for dissemination and establishment of a systemic infection. Understanding how pathogens overcome these innate defenses is important for the development of optimal therapeutic strategies for invasive infections. Furthermore S. iniae proves to be a powerful model to investigate bacterial adaptations during systemic streptococcal infection.
Allen, Jonathan Paul, "Pleiotropic regulatory function of the lysr family transcriptional regulator cpsy during streptococcus iniae systemic infection" (2011). Wayne State University Dissertations. 300.