Abstract
Neutrophils release free zinc to eliminate the phagocytosed bacterial pathogen Streptococcus pyogenes (Group A Streptococcus; GAS). In this study, we investigated the mechanisms underpinning zinc toxicity towards this human pathogen, responsible for diseases ranging from pharyngitis and impetigo, to severe invasive infections. Using the globally-disseminated M1T1 GAS strain, we demonstrate that zinc stress impairs glucose metabolism through the inhibition of the glycolytic enzymes phosphofructokinase and glyceraldehyde-3-phosphate dehydrogenase. In the presence of zinc, a metabolic shift to the tagatose-6-phosphate pathway allows conversion of D-galactose to dihydroxyacetone phosphate and glyceraldehyde phosphate, partially bypassing impaired glycolytic enzymes to generate pyruvate. Additionally, zinc inhibition of phosphoglucomutase results in decreased capsule biosynthesis. These data indicate that zinc exerts it toxicity via mechanisms that inhibit both GAS central carbon metabolism and virulence pathways.
Highlights
Neutrophils release free zinc to eliminate the phagocytosed bacterial pathogen Streptococcus pyogenes (Group A Streptococcus; GAS)
Calprotectin has a high affinity for zinc and the sequestration of this critical metal ion leads to starvation of the bacterial pathogen[5]
Our findings indicate that elevated zinc disrupts virulence through the reduction of hyaluronic acid capsule biosynthesis
Summary
Neutrophils release free zinc to eliminate the phagocytosed bacterial pathogen Streptococcus pyogenes (Group A Streptococcus; GAS). Zinc inhibition of phosphoglucomutase results in decreased capsule biosynthesis These data indicate that zinc exerts it toxicity via mechanisms that inhibit both GAS central carbon metabolism and virulence pathways. Zinc is a significant factor in the innate immune defence against pathogens[1] This metal ion is an absolute nutritional requirement for the growth of all cells and it is essential for the activity of a wide variety of enzymes[2]. Deletion of czcD resulted in reduced virulence in a murine infection model of GAS invasive disease[10] These data are consistent with a direct antimicrobial effect of zinc on bacteria during infection. Zinc inhibits key enzymes of glucose catabolism, leading to a shift in expression of central carbon catabolic pathways
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