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Abstract
Zwitterionic polysaccharide (ZPS) components of the bacterial cell envelope have been shown to exert a major histocompatibility complex (MHC) II-dependent activation of CD4+ T cells, which in turn can modulate the outcome and progression of infections in animal models. We investigated the impact of zwitterionic cell wall teichoic acid (WTA) produced by Staphylococcus aureus on the development of skin abscesses in a mouse model. We also compared the relative biological activities of WTA and capsular polysaccharide (CP), important S. aureus pathogenicity factors, in abscess formation. Expression of both WTA and CP markedly affected the ability of S. aureus to induce skin abscess formation in mice. Purified wild-type zwitterionic WTA was more active in inducing abscess formation than negatively charged mutant WTA or purified CP8. To assess the ability of purified native WTA to stimulate T cell proliferation in vitro, we co-cultivated WTA with human T-cells and antigen presenting cells in the presence and absence of various inhibitors of MHC-II presentation. Wild-type WTA induced T cell proliferation to a significantly greater extent than negatively charged WTA. T cell activation was dependent on the presentation of WTA on MHC II, since inhibitors of MHC II-dependent presentation and antibodies to MHC II significantly reduced T cell proliferation. T cells activated in vitro with wild-type WTA, but not negatively charged WTA, induced abscess formation when injected subcutaneously into wild-type mice. CD4−/− mice similarly injected with WTA failed to develop abscesses. Our results demonstrate that the zwitterionic WTA of S. aureus induces CD4+ T-cell proliferation in an MHCII-dependent manner, which in turn modulates abscess formation in a mouse skin infection model. An understanding of this novel T cell-dependent host response to staphylococcal abscess formation may lead to the development of new strategies to combat S. aureus skin and soft tissue infections.
Highlights
Wall teichoic acid (WTA) of Staphylococcus aureus is a zwitterionic cell wall glycopolymer composed of,40 ribitol phosphate repeating units modified with N-acetylglucosamine and D-alanine [1,2]
Since bacterial Zwitterionic polysaccharide (ZPS) are associated with abscess formation [12,29], we explored the contribution of zwitterionic WTA and capsular polysaccharide (CP) in a mouse skin infection model
To assess the relative roles played by S. aureus WTA and CPs in skin infections, we transduced the tagO mutation into the capsule type 5 (CP5)+ strain Newman and its isogenic acapsular cap5O mutant
Summary
Wall teichoic acid (WTA) of Staphylococcus aureus is a zwitterionic cell wall glycopolymer composed of ,40 ribitol phosphate repeating units modified with N-acetylglucosamine and D-alanine [1,2]. The negatively charged phosphate groups in the ribitol repeating unit and the ester-linked D-alanine residues contribute to the zwitterionic charge of WTA (Fig. 1). A S. aureus mutant lacking WTA showed attenuated virulence in a rabbit model of endocarditis [10]. Purified WTA was able to induce intraabdominal abscesses when rats were inoculated by the intraperitoneal route [12]. S. aureus mutants in the dlt operon, which mediates D-alanylation of WTA, exhibit a negatively charged cell surface and are more sensitive to cationic antimicrobial peptides than the parental strain [13,14]
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