lipoteichoic-acid and Staphylococcal-Skin-Infections

Staphylococcus aureus is a significant bacterial pathogen that may penetrate through the barrier into the epidermis and dermis of the skin. We hypothesized that the S. aureus cell wall product lipoteichoic acid (LTA) may contribute to the development of inflammation and skin barrier defects; however, the effects of LTA in vivo are not well understood. In this study, we examined the effects induced by intradermal S. aureus LTA. We found that keratinocytes in LTA-treated skin were highly proliferative, expressing 10-fold increased levels of Ki67. Furthermore, we observed that LTA caused damage to the skin barrier with substantial loss of filaggrin and loricrin expression. In addition, levels of the IL-1 family of inflammatory cytokines, as well as the neutrophil-attracting chemokines Cxcl1 and Cxcl2, were increased. Concomitantly, we observed significant numbers of neutrophils infiltrating into the epidermis. Finally, we determined that LTA-induced signals were mediated in part through IL-1, because an IL-1 receptor type 1 antagonist ameliorated the effects of LTA, blocking neutrophil recruitment and increasing the expression of skin barrier proteins. In summary, we show that S. aureus LTA alone is sufficient to promote keratinocyte proliferation, inhibit expression of epidermal barrier proteins, induce IL-1 signaling, and recruit cells involved in skin inflammation.

Topics: Animals; Cell Wall; Cells, Cultured; Cytoprotection; Disease Models, Animal; Epidermis; Filaggrin Proteins; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Keratinocytes; Ki-67 Antigen; Lipopolysaccharides; Mice; Neutrophil Infiltration; Neutrophils; Primary Cell Culture; Receptors, Interleukin-1 Type I; Staphylococcal Skin Infections; Staphylococcus aureus; Teichoic Acids

The cutaneous colonization with Staphylococcus aureus represents a potent trigger factor of atopic dermatitis. Toll-like receptor (TLR)-2 and CD36 have been shown to play a pivotal role in the internalization of staphylococcal components.. To investigate the impact of TLR-2 ligands on cell surface protein expression in monocytes from wild type (WT) AD patients and TLR-2 R753Q polymorph AD patients.. CD36 expression was significantly less downregulated in TLR-2 polymorph AD patients compared to wild type AD patients upon stimulation with peptidoglycan (PGN) and lipoteichoic acid (LTA) and compared to healthy controls upon stimulation with PGN. Expression of CD86 was higher upon N-palmitoyl-S-[2,3-bis(palmitoyl)-(2RS)-propyl]-(R)cysteinyl-alanyl-glycine (Pam3Cys) stimulation in TLR-2 R753Q polymorph AD patients compared to wild type AD patients. Expression of CD80 and CD54 were unaffected.. The differences in CD36 expression in TLR-2 polymorph AD patients compared to wild type AD patients and healthy controls may be associated with an enhanced susceptibility to skin infections with S. aureus.

Topics: Case-Control Studies; CD36 Antigens; Dermatitis, Atopic; Disease Susceptibility; Humans; Ligands; Lipopolysaccharides; Monocytes; Peptidoglycan; Polymorphism, Single Nucleotide; Skin; Staphylococcal Skin Infections; Staphylococcus aureus; Teichoic Acids; Toll-Like Receptor 2

Bacterial infection with Staphylococcus aureus is a known trigger for worsening of atopic dermatitis (AD); the exact mechanisms by which bacterial infection worsens dermatitis are unknown.. We sought to characterize the amounts of the biologically active bacterial lipoprotein lipoteichoic acid (LTA) in infected AD lesions.. Eighty-nine children with clinically impetiginized lesions of AD were enrolled in this study. A lesion was graded clinically by using the Eczema Area and Severity Index (EASI), wash fluid obtained from the lesion for quantitative bacterial culture, and measurement of LTA and cytokines. The staphylococcal isolate was tested for antibiotic susceptibilities. The patients were treated with a regimen that included topical corticosteroids and systemic antibiotics, and the lesion was reanalyzed after 2 weeks.. S aureus was identified in 79 of 89 children enrolled in the study. The bacterial colony-forming unit (CFU) counts correlated with the EASI lesional score (P = .04). LTA levels as high as 9.8 mug/mL were measured in the wash fluid samples, and the amounts correlated with the lesional EASI scores (P = .01) and S aureus CFU (P < .001). Approximately 30% of clinically impetiginized AD lesions contained greater than 1 mug/mL LTA, amounts that exert effects on various cell types in vitro. Moreover, injection of skin tissue ex vivo with amounts of LTA found in AD lesions resulted in epidermal cytokine gene expression.. Pharmacologic levels of LTA are found in many infected atopic dermatitis lesions.

Topics: Child; Child, Preschool; Colony Count, Microbial; Dermatitis, Atopic; Eczema; Humans; Infant; Interleukin-8; Lipopolysaccharides; Severity of Illness Index; Skin; Staphylococcal Skin Infections; Staphylococcus aureus; Teichoic Acids; Tumor Necrosis Factor-alpha

Staphylococcus aureus is a significant human pathogen that can colonize the skin. Neutrophils are well known to be involved in clearance of the bacterium. This study focused on exploring the role that human keratinocytes have as first responders to bacterial challenges. IL-1alpha and IL-1beta increased mRNA production and protein secretion of the neutrophil chemotactic CXCL1, CXCL2, and IL-8 in keratinocytes. S. aureus and the bacterial cell wall components lipoteichoic acid (LTA) and peptidoglycan (PGN) induced similar expression profiles in a Toll-like receptor (TLR)-2-dependent manner. Interestingly, the S. aureus-induced mRNA levels peaked at later time points than those induced by IL-1. The S. aureus-activated chemokine production was preceded by significant IL-1alpha and IL-1beta secretion. Expression of IL-1alpha was significantly higher than that of IL-1beta. Inhibition of IL-1RI using neutralizing antibodies revealed that S. aureus-derived LTA and PGN-induced chemokine expression requires IL-1RI engagement. Surprisingly, we further found that chemokine secretion is dependent upon endocrine IL-1alpha, but not IL-1beta, signaling. Our data show that the innate immune response of keratinocytes is regulated differently than those of other cell types. This may represent a fail-safe system that protects the host against genetic variation and immune evasion mechanisms developed by pathogens.

Topics: Antibodies, Neutralizing; Autocrine Communication; Cell Wall; Cells, Cultured; Chemokine CXCL1; Chemokine CXCL2; Chemotaxis, Leukocyte; Humans; Interleukin-1alpha; Interleukin-1beta; Interleukin-8; Keratinocytes; Lipopolysaccharides; Neutrophils; Oligonucleotide Array Sequence Analysis; Peptidoglycan; Receptors, Interleukin-1; RNA, Messenger; Signal Transduction; Staphylococcal Skin Infections; Staphylococcus aureus; Teichoic Acids; Toll-Like Receptor 2

Stratum corneum (SC) exerts a proinflammatory effect in the presence of complement. When Staphylococcus aureus (S. aureus) invades the skin through damaged SC, neutrophils accumulate at the subcorneal portion of epidermis to phagocytize the S. aureus as noted in impetigo. Besides the phagocytosis of bacteria, neutrophils interact with opsonized SC in a form of frustrated phagocytosis, increasing a damage of the surrounding tissues. Based on our previous finding that staphylococcal protein A promotes the interaction between SC and neutrophils, we investigated whether lipoteichoic acid (LTA), another cell wall component of S. aureus, also shows similar properties. We found that LTA significantly promoted the binding of neutrophils to opsonized SC, resulting in an increase in SC-induced respiratory burst of neutrophils assessed by chemiluminescence (CL). The binding of neutrophils to the SC was almost completely inhibited by the blocking of CR3 with anti-CD11b antibody, suggesting that the binding between SC and neutrophils is mediated by interaction between C3bi and CR3 (Mac-1). Such enhanced interaction seems to function in the primary host defence mechanism against the invading S. aureus through the skin such as in impetigo.

Topics: Antibodies, Monoclonal; Antigens, CD; CD11 Antigens; Cell Wall; Complement C3b; Complement Pathway, Alternative; Epidermal Cells; Humans; Lipopolysaccharides; Luminescent Measurements; Macrophage-1 Antigen; Neutrophils; Opsonin Proteins; Phagocytosis; Receptors, Complement; Respiratory Burst; Staphylococcal Skin Infections; Staphylococcus aureus; Teichoic Acids