Elucidating the Role of MRSA SasF in Skin Colonization and Disease

Staphylococcus aureus and its methicillin-resistant derivative (MRSA) are the top causative agent of skin and soft tissue infections globally. Though the pathogenic potential of MRSA is unparalleled, approximately 30% of all humans are asymptomatically colonized with S. aureus, mainly in the anterior nares. This colonization by S. aureus is directly correlated to an increased infection probability at multiple sites, making colonization an important step in the S. aureus pathogenic lifestyle. Though S. aureus colonizes a significant portion of the population, a comprehensive understanding of all the factors used by S. aureus to colonize the skin remain unknown. This proposal aims at characterizing the hypothetical protein SasF, and its role in skin MRSA skin colonization and pathogenesis. Previously, our group has performed an RNAseq experiment aimed at assessing MRSA transcriptomic changes that ensue following colonization of healthy murine skin. In this experiment, we observed that sasF was significantly upregulated at both 5- and 24-hours post-colonization. In preliminary studies, we have shown that MRSA SasF is involved in providing MRSA with protection against antimicrobial lipids that are readily found within the skin barrier. We have also shown that a MRSA mutant lacking the capacity to produce SasF is greatly hindered in virulence in a skin-abscess infection model. This proposal seeks to understand how SasF contributes to host skin colonization and infection, and how SasF may mechanistically protect MRSA against these host skin lipids. I hypothesize that SasF protects MRSA against host antimicrobial lipids through charge differences in the wall teichoic acids, and that SasF-mediated cell surface charge modulation provides MRSA with the crucial ability to colonize and infect the skin of a host. These hypotheses will be tested both biochemically and within the context of a host-environments by a variety of in vitro and in vivo biochemical and infection-model approaches in these specific aims: Aim 1: Determine the role of SasF in host colonization and infection and Aim 2: Determine how SasF protects MRSA from skin relevant antimicrobial lipids via the modification of the cell surface charge. In all, the data generated from this proposal will not only increase our collective knowledge of the factors required for S. aureus to colonize and infect skin but will also generate crucial data characterizing how bacteria overcome innate host-lipid defenses. Furthermore, this proposal may help to reveal SasF as a novel antimicrobial therapeutic target which could be used as a target for not only preventing S. aureus skin colonization, but also managing clinically relevant and difficult to treat MRSA infections. Project Number: 1F31AI183751-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Timothy Enroth | Institution: UNIVERSITY OF COLORADO DENVER, Aurora, CO | Award Amount: $38,093 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F07A-M (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31AI18375101A1