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 Contributions
Abstract 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.
Funding
This research was funded by NIH grant number T32AR007534-36.
Institutional Review Board Statement
The animal study protocol was approved by the Institutional Review Board of the University of Colorado (Protocol 0941, Approved 31 October 2022).
Informed Consent Statement
Not applicable.
Data Availability Statement
Datasets available on request from the authors.
Conflicts of Interest
The authors declare no conflicts of interest.
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