| Autor: |
Davis SE; Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA., Hart MT; Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA., Braza RED; Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA., Perry AA; Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA., Vega LA; Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA., Le Breton YS; Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA., McIver KS; Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland, USA. |
| Abstrakt: |
Streptococcus pyogenes (Group A Streptococcus , GAS) is a Gram-positive bacterium that inflicts both superficial and life-threatening diseases on its human host. Analysis of fitness using a transposon mutant library revealed that genes predicted to be involved in vitamin B 6 acquisition are associated with fitness in whole human blood. Vitamin B 6 is essential for all life and is important for many cellular functions. In several streptococcal species, it has been shown that mutants in B 6 acquisition exhibited reduced virulence phenotypes and were attenuated during infection. In GAS, B 6 acquisition is believed to be controlled by the pdxR-pdxKU locus, where PdxR is a positive regulator of pdxKU , which encodes for a B 6 -substrate kinase and permease, respectively. Mutants in the regulator (Δ pdxR ) and salvage machinery (Δ pdxKU ) both exhibited modest growth defects when grown in oxygenated conditions with limited vitamin B 6 precursors. ∆ pdxR and ∆ pdxKU mutants also exhibited an impaired ability to survive when challenged with whole human or mouse blood. This defect was characterized by reduced survival in the presence of human neutrophil-like HL60s, primary polymorphonuclear leukocytes, and antimicrobial peptide LL-37. Promoter analysis showed that PdxR is an autoregulator and activated pdxKU in the absence of B 6 . Interestingly, ∆ pdxR and ∆ pdxKU mutants were not attenuated in mouse models of infection, suggesting a species-specific impact on virulence. Overall, it appears that pdxR-pdxKU is associated with GAS vitamin B 6 metabolism as well as pathogen survival during encounters with the human innate immune system.IMPORTANCEBacterial pathogens such as Streptococcus pyogenes (Group A Streptococcus , GAS) must be able to obtain needed nutrients in their human host. Vitamin B 6 or pyridoxal 5' phosphate is essential for all life and is important for many cellular functions. In other streptococcal pathogens, B 6 acquisition has been shown to be important for their ability to cause disease. Here, we show that loss of the putative vitamin B 6 salvage pathway locus pdxR-pdxKU affects GAS pathogenesis when encountering innate immune responses from phagocytic neutrophils and antimicrobial peptides within the host. pdxR- pdxKU may contribute to oxygen tolerance through B 6 ; however, there appear to be other mechanisms for salvaging vitamin B 6 . Overall, pdxR-pdxKU is associated with GAS resistance to the human innate immune response and oxygen tolerance and contributes modestly to B 6 metabolism. |
