GAS Regulation of Zinc Homeostasis During Skin and Soft Tissue Infection

first_page Download PDF settings Order Article Reprints Font Type: Arial Georgia Verdana Font Size: Aa Aa Aa Line Spacing:    Column Width:    Background: Open AccessAbstract GAS Regulation of Zinc Homeostasis During Skin and Soft Tissue Infection † by Reid WilkeningReid Wilkening SciProfiles Scilit Preprints.org Google Scholar 1,2,*, Lindsey BurchamLindsey Burcham SciProfiles Scilit Preprints.org Google Scholar 3, Laura CookLaura Cook SciProfiles Scilit Preprints.org Google Scholar 4 and Alexander HorswillAlexander Horswill SciProfiles Scilit Preprints.org Google Scholar 2 1 Department of Pediatrics, Section of Pediatric Critical Care Medicine, University of Colorado, Aurora, CO 80045, USA 2 Department of Microbiology and Immunology, University of Colorado, Aurora, CO 80045, USA 3 Department of Microbiology, University of Tennessee, Knoxville, TN 37996, USA 4 Binghamton Biofilm Research Center, Department of Biology, Binghamton University, Binghamton, NY 13902, USA * Author to whom correspondence should be addressed. † Presented at the 22nd Lancefield International Symposium on Streptococci and Streptococcal Diseases, Brisbane, Australia, 1–5 June 2025. Proceedings 2025, 124(1), 17; https://doi.org/10.3390/proceedings2025124017 Published: 15 August 2025 (This article belongs to the Proceedings of The 22nd Lancefield International Symposium on Streptococci and Streptococcal Diseases (LISSSD 2025)) Download keyboard_arrow_down Download PDF Download PDF with Cover Download XML Download Epub Versions Notes Keywords: Streptococcus pyogenes; host-pathogen interaction; metal homeostasis; sRNA Streptococcus pyogenes (Group A Streptococcus, GAS) is an enigmatic human-restricted pathobiont, capable of both colonization and infection. Illnesses range in severity from superficial to invasive disease. GAS is also the causative agent of non-suppurative sequelae including acute rheumatic fever (ARF) and rheumatic heart disease (RHD), both significant global sources of morbidity and mortality. While historically it has been thought that GAS pharyngitis leads to ARF/RFH, current data better support the hypothesis that superficial skin infections (e.g., impetigo or cellulitis) are incipient to ARF/RHD, making it critical to understand the mechanisms of skin infection. We have developed and validated a murine model mimicking the early stages of GAS skin infection. Using RNA sequencing, we have identified genes critical for skin infection, including an intriguing proposed dual-acting small RNA (sr0235) and peptide (0235c) pair that is significantly upregulated during skin infection. In this pair, a proposed sRNA encompasses a standalone open reading frame and promoter. The in silico analysis of this locus suggests that the pair is involved in zinc homeostasis and finds broad conservation across GAS and Streptococcus agalactiae. In vitro studies demonstrate that the absence of this pair impairs growth under zinc-limited conditions, with peptide expression induced during zinc chelation. While additional studies are needed to understand the unique functions of the peptide and sRNA, these results have led to the hypothesis that this sRNA/peptide pair plays a critical role in infecting zinc-poor epithelial surfaces and may allow us to detangle critical early interactions leading to skin infections. Author ContributionsAbstract preparation, R.W.; conceptualization, R.W., L.B., L.C. and A.H.; methodology, R.W., L.C. and L.B. All authors have read and agreed to the published version of the manuscript.FundingThis research was funded by NIH grant number T32AR007534-36.Institutional Review Board StatementThe animal study protocol was approved by the Institutional Review Board of the University of Colorado (Protocol 0941, Approved 31 October 2022).Informed Consent StatementNot applicable.Data Availability StatementDatasets available on request from the authors.Conflicts of InterestThe authors declare no conflicts of interest.Disclaimer/Publisher's Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Share and Cite MDPI and ACS Style Wilkening, R.; Burcham, L.; Cook, L.; Horswill, A. GAS Regulation of Zinc Homeostasis During Skin and Soft Tissue Infection. Proceedings 2025, 124, 17. https://doi.org/10.3390/proceedings2025124017 AMA Style Wilkening R, Burcham L, Cook L, Horswill A. GAS Regulation of Zinc Homeostasis During Skin and Soft Tissue Infection. Proceedings. 2025; 124(1):17. https://doi.org/10.3390/proceedings2025124017 Chicago/Turabian Style Wilkening, Reid, Lindsey Burcham, Laura Cook, and Alexander Horswill. 2025. "GAS Regulation of Zinc Homeostasis During Skin and Soft Tissue Infection" Proceedings 124, no. 1: 17. https://doi.org/10.3390/proceedings2025124017 APA Style Wilkening, R., Burcham, L., Cook, L., & Horswill, A. (2025). 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