Staphylococcus aureus is a commensal bacterium that colonizes about 30% of the population without any harmful effects. However, S. aureus also represents a major public health concern, due to its ability to cause a wide range of clinical infections combined with the alarming development of antibiotic resistance, which limits treatment options. One of the prime targets for the development of new therapeutic interventions against S. aureus the wall teichoic acids (WTAs), which are abundant glycopolymers that are critical for bacterial physiology, antibiotic resistance and colonization. Commonly, S. aureus expresses WTA composed of a polyribitol-phosphate backbone modified by D-alanine. Structural variation is limited and occurs through glycosylation by the activity of three distinct enzymes: TarM, TarS and TarP [1-2]. Through a multidisciplinary approach, including genetics, microbiology, immunology, and glycobiology, we aim to unravel the molecular interplay between WTAs and host immunity to advance the development of new antimicrobial therapies targeting.
This presentation will highlight some of our recent findings in this area. First, we have identified human Langerin, a receptor unique to skin epidermal Langerhans cells (LCs), as a receptor for β-linked GlcNAc on S. aureus WTA. Functionally, LCs respond with increased cytokine production to S. aureus that express β-GlcNAc-modified WTA. Finally, in a murine epicutaneous infection model, S. aureus strongly upregulated transcript specific cytokine transcripts, which required the presence of both human langerin and WTA β-GlcNAc . Together, these findings provide molecular insight into the unique pro-inflammatory capacities of S. aureus in relation to skin inflammation. The second project demonstrates how the use of chemically synthesized polyribitol-phosphate molecules helps to dissect interactions between WTA and human immune components, specifically human antibodies. In the future, these synthetic WTA molecules will be applied to provide structural insights but could also serve as a platform for identification and optimization of therapeutic antibodies directed against S. aureus WTA.