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Salivary Antimicrobial Peptide Histatin-5 Does Not Display Zn(II)-Dependent or -Independent Activity against Streptococci

Stewart, Louisa J.; Hong, YoungJin; Holmes, Isabel R.; Firth, Samantha J.; Ahmed, Yasmin; Quinn, Janet; Santos, Yazmin; Cobb, Steven L.; Jakubovics, Nicholas S.; Djoko, Karrera Y.

Salivary Antimicrobial Peptide Histatin-5 Does Not Display Zn(II)-Dependent or -Independent Activity against Streptococci Thumbnail


Authors

Louisa J. Stewart

YoungJin Hong

Isabel R. Holmes

Yasmin Ahmed

Janet Quinn

Nicholas S. Jakubovics



Abstract

Histatin-5 (Hst5) is a member of the histatin superfamily of cationic, His-rich, Zn(II)-binding peptides in human saliva. Hst5 displays antimicrobial activity against fungal and bacterial pathogens, often in a Zn(II)-dependent manner. In contrast, here we showed that under in vitro conditions that are characteristic of human saliva, Hst5 does not kill seven streptococcal species that normally colonize the human oral cavity and oropharynx. We further showed that Zn(II) does not influence this outcome. We then hypothesized that Hst5 exerts more subtle effects on streptococci by modulating Zn(II) availability. We initially proposed that Hst5 contributes to nutritional immunity by limiting nutrient Zn(II) availability and promoting bacterial Zn(II) starvation. By examining the interactions between Hst5 and Streptococcus pyogenes as a model Streptococcus species, we showed that Hst5 does not influence the expression of Zn(II) uptake genes. In addition, Hst5 did not suppress growth of a ΔadcAI mutant strain that is impaired in Zn(II) uptake. These observations establish that Hst5 does not promote Zn(II) starvation. Biochemical examination of purified peptides further confirmed that Hst5 binds Zn(II) with high micromolar affinities and does not compete with the AdcAI high-affinity Zn(II) uptake protein for binding nutrient Zn(II). Instead, we showed that Hst5 weakly limits the availability of excess Zn(II) and suppresses Zn(II) toxicity to a ΔczcD mutant strain that is impaired in Zn(II) efflux. Altogether, our findings led us to reconsider the function of Hst5 as a salivary antimicrobial agent and the role of Zn(II) in Hst5 function.

Citation

Stewart, L. J., Hong, Y., Holmes, I. R., Firth, S. J., Ahmed, Y., Quinn, J., …Djoko, K. Y. (2023). Salivary Antimicrobial Peptide Histatin-5 Does Not Display Zn(II)-Dependent or -Independent Activity against Streptococci. ACS Infectious Diseases, 9(3), 631-642. https://doi.org/10.1021/acsinfecdis.2c00578

Journal Article Type Article
Online Publication Date Feb 24, 2023
Publication Date 2023
Deposit Date Apr 27, 2023
Publicly Available Date Apr 28, 2023
Journal ACS Infectious Diseases
Electronic ISSN 2373-8227
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 9
Issue 3
Pages 631-642
DOI https://doi.org/10.1021/acsinfecdis.2c00578
Public URL https://durham-repository.worktribe.com/output/1175483

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