More than 25% of the human population are colonized with Staphylococcus aureus. Although colonization is often asymptomatic, S. aureus carriage leads to an increased risk in developing severe invasive infections such as lethal sepsis and infective endocarditis (IE) and S. aureus is now the predominant causative pathogen involved in 15-40% of all IE cases. S. aureus responds to environmental changes by altering its transcriptional profile. Recent studies demonstrated that hla transcription, the gene encoding the cytolysin alpha-toxin, is upregulated in a S. aureus USA300 strain after transition of the bacterium from the bloodstream to the heart tissue, indicating a crucial role of this cytolysin in IE. I have focused on linear peptide signaling in S. aureus, with an emphasis on the camS gene, which encodes the linear peptide staph-cAM373 and the CamS lipoprotein. To this point, we have identified the processing and secretion cascade responsible for the production and release of staph-cAM373. In addition, my preliminary data shows that camS is also involved in S. aureus virulence. I was able to link this phenotype to a regulatory role of camS on alpha-toxin production and differential expression of the heme uptake system. Based on my preliminary data and the iron-limiting nature of the heart, I propose that camS governs the transition of S. aureus from a commensal bacterium to a pathogen by acting as a repressor of important virulence factors, including alpha-toxin and iron transporters. Initially I will determine which part of camS, either staph-cAM373 or the CamS lipoprotein, is the active regulatory component. I will also determine the influence of camS on the fitness of S. aureus under iron limiting conditions, a situation encountered in the heart. In a next step, I will test whether camS mediated regulation is conserved among clinical isolates and finally I will determine the importance of camS virulence regulation in vivo by using animal models of skin and soft tissue infections and infective endocarditis.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|