Inflammatory Joint Disease Is a Risk Factor for Streptococcal Sepsis and Septic Arthritis in Mice.

Johann Volzke,Marcel Kordt,Wendy Bergmann,Michael Müller,Daniel Schultz,Karen Methling,Bernd Kreikemeyer,Brigitte Müller-Hilke

doi:10.3389/fimmu.2020.579475

Abstract

Septic arthritis is a medical emergency associated with high morbidity and mortality, yet hardly any novel advances exist for its clinical management. Despite septic arthritis being a global health burden, experimental data uncovering its etiopathogenesis remain scarce. In particular, any interplay between septic arthritis and preceding joint diseases are unknown as is the contribution of the synovial membrane to the onset of inflammation. Using C57BL/6 mice as a model to study sepsis, we discovered that Group A Streptococcus (GAS) – an important pathogen causing septic arthritis - was able to invade the articular microenvironment. Bacterial invasion resulted in the infiltration of immune cells and detrimental inflammation. In vitro infected fibroblast-like synoviocytes induced the expression of chemokines (Ccl2, Cxcl2), inflammatory cytokines (Tnf, Il6), and integrin ligands (ICAM-1, VCAM-1). Apart from orchestrating immune cell attraction and retention, synoviocytes also upregulated mediators impacting on bone remodeling (Rankl) and cartilage integrity (Mmp13). Using collagen-induced arthritis in DBA/1 × B10.Q F1 mice, we could show that an inflammatory joint disease exacerbated subsequent septic arthritis which was associated with an excessive release of cytokines and eicosanoids. Importantly, the severity of joint inflammation controlled the extent of bone erosions during septic arthritis. In order to ameliorate septic arthritis, our results suggest that targeting synoviocytes might be a promising approach when treating patients with inflammatory joint disease for sepsis.

Highlights

Streptococcus pyogenes (Group A Streptococcus, GAS) is a gram-positive pathogen causing a wide variety of usually non-severe disorders like impetigo and pharyngitis [1]
We here demonstrated that inflammatory joint disease posed a risk for Streptococcal sepsis and septic arthritis in mice
Pre-existing collagen induced arthritis (CIA) significantly reduced survival of subsequent GAS infection and significantly increased incidence of septic arthritis (SA) with both, synovial fibroblasts and immune cells contributing to the disease process

Summary

Introduction

Streptococcus pyogenes (Group A Streptococcus, GAS) is a gram-positive pathogen causing a wide variety of usually non-severe disorders like impetigo and pharyngitis [1]. GAS can turn into a severe threat. GAS can proficiently subvert the immune response of the host by, for example, inducing apoptosis in immune cells [5] and degrading neutrophil extracellular traps [6]. It causes severe bacteremia resulting in a broad collection of critical conditions [7]. As there is no vaccine against this pathogen [9], therapies need to be improved which in turn requires a better understanding of the pathological manifestations leading to severe disease courses like streptococcal toxic shock syndrome, necrotizing fasciitis, and septic arthritis (SA)

Methods

Results

Conclusion