# Investigating CovRS activation within skin microenvironments to drive heterogenicity of Streptococcus pyogenes gene expression > **NIH NIH F31** · EMORY UNIVERSITY · 2023 · $47,694 ## Abstract ABSTRACT Streptococcus pyogenes infections are a major burden to the healthcare system in the United States and globally. Most infections are mild and superficial, such as pharyngitis and impetigo. However, rapid disease progression may result in life-threatening invasive infections, such as necrotizing fasciitis and toxic shock syndrome. Furthermore, recovered patients often suffer post-infection chronic complications, including acute rheumatic heart disease. Altogether, S. pyogenes infections and post-infection complications result in more than 600,000 global deaths annually. Currently, there is no vaccine against S. pyogenes and high instances of morbidity and mortality highlight the urgent need for alternative treatment strategies. Unlike most pathogens, S. pyogenes thrives in inflammatory environments by expressing virulence factors that promote immune evasion, which is often associated with invasive infections. Approximately 15% of the genome, including most virulence factors, is regulated by a two-component system called CovRS (or CsrRS). CovRS detects the host peptide LL- 37, which functions as a potent signal for virulence factor regulation. However, it remains unclear how changes in LL-37 availability due to cell death alters CovRS regulation during the progression of an infection. Further, distinct toxins of S. pyogenes are expressed in CovRS “on/off” activity states, yet all are essential during infection. This indicates that sub-populations of genetically identical bacteria in different CovRS “on/off” states may release varying toxins during different stages of infection and within distinct microenvironments that collectively contribute to pathogenesis. I hypothesize that heterogenous CovRS regulation is controlled by variations of LL- 37 levels due to inflammatory cell death, allowing heterogenous toxin production necessary for S. pyogenes infections. I will test my hypothesis by 1) using genetics techniques within the host and pathogen to identify how inflammatory cell death impacts LL-37 release and CovRS regulons, and 2) using microscopy for single cell analysis to examine how local LL-37 concentration contributes to CovRS signaling in engineered S. pyogenes reporter strains. Collectively, these studies will provide insight into the mechanisms responsible for S. pyogenes- induced inflammation and identify novel drug targets that stall disease progression. ## Key facts - **NIH application ID:** 10751462 - **Project number:** 1F31AI179103-01 - **Recipient organization:** EMORY UNIVERSITY - **Principal Investigator:** Stephanie Corinne Guerra - **Activity code:** F31 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2023 - **Award amount:** $47,694 - **Award type:** 1 - **Project period:** 2023-09-01 → 2026-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10751462 ## Citation > US National Institutes of Health, RePORTER application 10751462, Investigating CovRS activation within skin microenvironments to drive heterogenicity of Streptococcus pyogenes gene expression (1F31AI179103-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10751462. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*