Staphylococci through the human body : molecular analysis of SdrD and Aap adhesins in attachment processes
(2024)
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- Authors
- Supervisors
- Dufrêne, Yves
- Abstract
- Staphylococci, especially Staphylococcus aureus and Staphylococcus epidermidis, have caused since the 40’s an increasing burden of infections. The main response to tackle it was, for a long-time, antibiotics. Nevertheless, we face nowadays more and more cases of resistance making these treatments ineffective. Despite multiple attempts, robust alternative strategies are still missing, highlighting the growing need for new therapies. These pathogens are indeed extremely well equipped to colonize their host. By means of various virulence factors, they establish finely tuned infections. Among them, the adhesins are surface proteins allowing the bacteria to specifically adhere to their host. while biofilms embed bacteria in a protective and communal matrix. In this context, this thesis used single- molecule and single-cell force spectroscopy-based atomic force microscopy to shed light on the mechanical and biophysical properties of the interactions established between staphylococcal adhesins (i.e. S. aureus SdrD and S. epidermidis Aap) and their host ligands in different relevant body environments. First, we studied the human skin, where a competition occurs between S. aureus and S. epidermidis. We revealed the nature of the ligand, i.e. desmoglein-1 (DSG-1) for SdrD A domain and glycoproteins for Aap lectin domain, as well as the high forces mechanisms they engage. SdrD binding is enhanced by physical stress, calcium and the unusual role of DSG-1 cadherin domain EC4. It is also increased towards atopic dermatitis skin, thereby participating to the worsening of this skin disease. On its side, Aap engages its ligand following a bipartite interaction thanks to unique mechanical properties of the unusual B-repeat protein fold. Then, we highlighted the extreme resilience S. epidermidis displays while binding (through its Aap A domain) to the vWF protein in the blood, notably due to the involvement of the two distant A and B domains of Aap following an allosteric mechanism. Finally, we discovered that Aap is involved in two distinct complexes (first heterophilic interaction between its lectin A subdomain and a carbohydrate ligand and then strong B domain-mediated homophilic bonds featuring surprisingly high-force unfolding of the B domain) during S. epidermidis zinc-dependent biofilm formation. Altogether, these results could provide a great start point for the design of anti-adhesion therapies proposing to block the adhesins.
- Affiliations
Citations
Chantraine, C. (2024). Staphylococci through the human body : molecular analysis of SdrD and Aap adhesins in attachment processes. https://hdl.handle.net/2078.5/241947