The initial step in colonization or infection requires attachment of S. aureus to skin surfaces. The skin of patients with AD has been demonstrated to have increased adherence for S. aureus.10 The reason for increased binding of S. aureus to AD skin is not completely understood but is thought to be due to the underlying skin inflammation. This concept is supported by the following studies:
1. Acute AD skin lesions are colonized with greater numbers of S. aureus than chronic skin lesions, unaffected atopic skin or normal non-atopic.3,4 Scratching probably enhances S. aureus binding by disturbing the skin barrier and releasing proinflam-matory cytokines which upregulate extracellular matrix molecules known to act as adhesins for S. aureus.11 Furthermore, cracks in the epidermal layer from scratching or skin dryness can expose underlying extracellular matrix molecules which can serve as an anchor for attachment of S. aureus to the skin.
2. It has been found that treatment with anti-inflammatory medications such as topical corticosteroids or tacrolimus significantly reduces the numbers of S. aureus found on atopic skin.12,13 Corticosteroids have no direct antimicrobial effects. Thus, it is very likely that atopic skin inflammation leads to the expression of attachment sites which promote colonization of S. aureus. Please see Table 5.1.
3. We have studied S. aureus binding to skin lesions in mice undergoing Th1-or Th2-mediated inflammatory responses.14 Bacterial binding to frozen skin sections was found to be significantly greater at skin sites with Th2-mediated inflammation than skin sites with Th1-mediated inflammation. Importantly this increased bacterial binding did not occur in IL-4 gene knockout mice suggesting that IL-4 plays a critical role in the enhancement of S. aureus binding to skin. Conversely when normal mouse skin was incubated in vitro with IL-4, as compared to inter-feron-gamma, increased S. aureus binding occurred only to skin explants treated with IL-4.
Recently, several staphylococcal cell surface molecules, termed 'adhesins' (aside from protein A), have been identified which are responsible for the initial interactions between S. aureus and extracellular matrix proteins in the skin. These include fibronectin-binding
Table 5.1 Factors contributing to S. aureus colonization/infection in atopic dermatitis
• Impaired skin barrier function
• Reduced skin lipid content in atopic dermatitis
• Skin surface pH toward alkalinity
• Increased skin adherence to S. aureus due to increased fibronectin and fibrinogen
• Decreased production of endogenous antimicrobial peptides (beta defensins, LL-37) by keratinocytes proteins A and B, clumping factors A and B which are fibrinogen-binding proteins, and collagen adhesins.11 Relevant to atopic inflammation, IL-4, but not inter-feron-gamma, is known to induce fibronectin production by skin fibroblasts.15
Recently, we found that fibronectin and fibrinogen, but not collagen, are involved in the binding of S. aureus to Th2-induced inflammatory skin lesions. This is supported by the following observations:
1. S. aureus mutants that were selectively deficient in fibronectin- or fibrinogen-binding proteins, as compared to their corresponding wild-type parent strains, demonstrated reduced binding to allergen-sensitised/challenged Th2, but not Th1, skin reactions in mice.14 Consistent with these studies, S. aureus mutants deficient in fibronectin- or fib-rinogen-binding proteins demonstrated reduced binding to human AD skin but not psoriatic skin or normal skin.16 In contrast, a S. aureus collagen adhesin-negative mutant did not show decreased binding to Th2-mediated inflamed skin.
2. When S. aureus was pre-incubated with either human serum albumin, fibronectin, collagen, or fib-rinogen in an attempt to block the S. aureus binding proteins, only fibronectin and fibrinogen significantly reduced the level of S. aureus binding to Th2-induced skin inflammation sites. Interestingly, the S. aureus binding sites were primarily confined to the stratum corneum.
Overall these data suggest a selective mechanism by which Th2, as compared to Th1, responses can enhance S. aureus binding to the skin. Thus, IL-4 induced fibronectin synthesis, in combination with plasma exudation of fibrinogen, could provide a mechanism by which the atopic/inflammatory environment mediates enhanced S. aureus attachment to the skin. Interestingly, the S. aureus fibronectin-binding MSCRAMM FnbpA is a bifunctional protein that also binds to fibrinogen.17
This observation is consistent with our observations suggesting that blocking the binding of S. aureus to fibrinogen and fibronectin may be an important therapeutic target for reduction of S. aureus colonization in atopic skin.
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