An antimicrobial role for zinc in innate immune defense against group A streptococcus.
BACKGROUND
Zinc plays an important role in human immunity, and it is known that zinc deficiency in the host is linked to increased susceptibility to bacterial infection. In this study, we investigate the role of zinc efflux in the pathogenesis of Streptococcus pyogenes (group A Streptococcus [GAS]), a human pathogen responsible for superficial infections, such as pharyngitis and impetigo, and severe invasive infections.


METHODS
The clinically important M1T1 wild-type strain was used in this study, and isogenic mutants were constructed with deletions in the czcD gene (Spy0653; which encodes a putative zinc efflux pump) and adjacent gczA gene (Spy0654; which encodes a putative zinc-dependent activator of czcD). Wild-type, isogenic mutants and complemented strains were tested for resistance against zinc stress, intracellular zinc accumulation, and virulence.


RESULTS
Both czcD and gczA mutants exhibited increased sensitivity to zinc. Transcriptional analyses indicate that GczA upregulates czcD in response to zinc. Both mutants displayed increased susceptibility to human neutrophil killing and reduced virulence in a murine infection model. Furthermore, we showed that neutrophils mobilize zinc in response to GAS.


CONCLUSIONS
These data indicate that the innate immune system may use zinc as an antimicrobial agent and that zinc efflux is an important contributor to GAS pathogenesis.
School of Chemistry and Molecular Biosciences.
Cheryl-lynn Y
CL
Ong
Christine M
CM
Gillen
Timothy C
TC
Barnett
Mark J
MJ
Walker
Alastair G
AG
McEwan
D001692:Biological Transport; D015964:Gene Expression Regulation, Bacterial / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D013290:Streptococcal Infections / Q000276:immunology* / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000235:genetics; D015032:Zinc / Q000378:metabolism*
D015032:Zinc
CzcD; Streptococcus pyogenes; group A Streptococcus; innate immunity; zinc efflux; zinc poisoning