TY - JOUR
T1 - An antimicrobial role for zinc in innate immune defense against group A streptococcus
AU - Ong, Cheryl Lynn Y.
AU - Gillen, Christine M.
AU - Barnett, Timothy C.
AU - Walker, Mark J.
AU - McEwan, Alastair G.
PY - 2014/5/15
Y1 - 2014/5/15
N2 - 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.
AB - 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.
KW - CzcD
KW - group A Streptococcus
KW - innate immunity
KW - Streptococcus pyogenes
KW - zinc efflux
KW - zinc poisoning
UR - http://www.scopus.com/inward/record.url?scp=84899503296&partnerID=8YFLogxK
U2 - 10.1093/infdis/jiu053
DO - 10.1093/infdis/jiu053
M3 - Article
C2 - 24449444
AN - SCOPUS:84899503296
VL - 209
SP - 1500
EP - 1508
JO - Journal Infectious Diseases
JF - Journal Infectious Diseases
SN - 0022-1899
IS - 10
ER -