Abstract
Staphylococcus aureus asymptomatically colonises the anterior nares, but the host and bacterial factors that facilitate colonisation remain incompletely understood. The S. aureus surface protein ClfB has been shown to mediate adherence to squamous epithelial cells in vitro and to promote nasal colonisation in both mice and humans. Here, we demonstrate that the squamous epithelial cell envelope protein loricrin represents the major target ligand for ClfB during S. aureus nasal colonisation. In vitro adherence assays indicated that bacteria expressing ClfB bound loricrin most likely by the “dock, lock and latch” mechanism. Using surface plasmon resonance we showed that ClfB bound cytokeratin 10 (K10), a structural protein of squamous epithelial cells, and loricrin with similar affinities that were in the low µM range. Loricrin is composed of three separate regions comprising GS-rich omega loops. Each loop was expressed separately and found to bind ClfB, However region 2 bound with highest affinity. To investigate if the specific interaction between ClfB and loricrin was sufficient to facilitate S. aureus nasal colonisation, we compared the ability of ClfB+ S. aureus to colonise the nares of wild-type and loricrin-deficient (Lor−/−) mice. In the absence of loricrin, S. aureus nasal colonisation was significantly impaired. Furthermore a ClfB− mutant colonised wild-type mice less efficiently than the parental ClfB+ strain whereas a similar lower level of colonisation was observed with both the parental strain and the ClfB− mutant in the Lor−/− mice. The ability of ClfB to support nasal colonisation by binding loricrin in vivo was confirmed by the ability of Lactococcus lactis expressing ClfB to be retained in the nares of WT mice but not in the Lor−/− mice. By combining in vitro biochemical analysis with animal model studies we have identified the squamous epithelial cell envelope protein loricrin as the target ligand for ClfB during nasal colonisation by S. aureus.
Highlights
Staphylococcus aureus is a commensal of humans that permanently colonises the anterior nares of about 20% of the population with the remainder being colonised transiently [1]
Proteins expressed on the surface of S. aureus, including clumping factor B (ClfB), are responsible for this interaction
A major component of the squamous epithelial cell envelope, represents the primary ligand for ClfB and that the interaction between ClfB and loricrin is required for efficient nasal colonisation by S. aureus
Summary
Staphylococcus aureus is a commensal of humans that permanently colonises the anterior nares of about 20% of the population with the remainder being colonised transiently [1]. Nasal carriage is an established risk factor for S. aureus infections both in the hospital and in the community with individuals often being infected with the strain that they carry [2,3,4]. Nasal carriage can be transiently eradicated by topical administration of the antibiotic mupirocin but this is compromised by the development of resistance [5]. Alternative strategies for reducing nasal carriage are required which will involve a detailed understanding of the molecular basis of interactions between the host and the bacterium that underlie the process. Host factors that determine nasal colonisation are incompletely understood. Polymorphisms in the genes encoding the glucocorticoid receptor, C-reactive proteins, interleukin-4 and complement inhibitor proteins have been associated with persistent nasal carriage [6,7,8]. The normal flora can influence the ability of S. aureus to colonise the nares [10,11]
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