Abstract
Bacterial biofilms represent a significant therapeutic challenge based on their ability to evade host immune and antibiotic-mediated clearance. Recent studies have implicated IL-1β in biofilm containment, whereas Toll-like receptors (TLRs) had no effect. This is intriguing, since both the IL-1 receptor (IL-1R) and most TLRs impinge on MyD88-dependent signaling pathways, yet the role of this key adaptor in modulating the host response to biofilm growth is unknown. Therefore, we examined the course of S. aureus catheter-associated biofilm infection in MyD88 knockout (KO) mice. MyD88 KO animals displayed significantly increased bacterial burdens on catheters and surrounding tissues during early infection, which coincided with enhanced dissemination to the heart and kidney compared to wild type (WT) mice. The expression of several proinflammatory mediators, including IL-6, IFN-γ, and CXCL1 was significantly reduced in MyD88 KO mice, primarily at the later stages of infection. Interestingly, immunofluorescence staining of biofilm-infected tissues revealed increased fibrosis in MyD88 KO mice concomitant with enhanced recruitment of alternatively activated M2 macrophages. Taken in the context of previous studies with IL-1β, TLR2, and TLR9 KO mice, the current report reveals that MyD88 signaling is a major effector pathway regulating fibrosis and macrophage polarization during biofilm formation. Together these findings represent a novel example of the divergence between TLR and MyD88 action in the context of S. aureus biofilm infection.
Highlights
Staphylococcus aureus (S. aureus) represents a major cause of both health care- and community-associated infections and with the increased prevalence of methicillin-resistant S. aureus (MRSA), this pathogen has become an even greater therapeutic challenge [1]
We evaluated the course of S. aureus biofilm growth and dissemination in MyD88 KO mice
Biofilm infections in MyD88 KO animals were associated with a significant reduction in the number of infiltrating macrophages at day 7 post-infection (Fig. 7), which were biased towards an anti-inflammatory/pro-fibrotic phenotype as revealed by a significant increase in CD206+ expression concomitant with decreased IRF-5+ levels (Fig. 8A and B, respectively). These findings demonstrate that MyD88-dependent signals regulate the balance of M1–M2 macrophage polarization during S. aureus biofilm infections and that loss of this adaptor activity leads to the preferential accumulation of M2 macrophages, which corroborates the enhanced fibrosis observed in biofilm infected tissues of MyD88 KO animals (Fig. 4)
Summary
Staphylococcus aureus (S. aureus) represents a major cause of both health care- and community-associated infections and with the increased prevalence of methicillin-resistant S. aureus (MRSA), this pathogen has become an even greater therapeutic challenge [1]. S. aureus biofilms are complex bacterial communities encased in a matrix composed primarily of polysaccharides, extracellular DNA (eDNA), and proteins [6,7,8,9] Many of these motifs are recognized by the innate immune system via the Toll-like receptor (TLR) family of pattern recognition receptors, which induces the secretion of numerous proinflammatory mediators that recruit and activate immune cell populations to sites of infection [10,11,12]. Recent evidence indicates that IL-1b plays a protective role during S. aureus biofilm formation in a postsurgical joint infection model [14] This is intriguing, since both TLRs and IL-1b converge on MyD88-dependent signaling pathways, which prompted our investigation into the functional impact of MyD88 during the course of S. aureus biofilm infection
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