The role of Staphylococcus aureus lipoproteins in hematogenous septic arthritis

Majd Mohammad,Rille Pullerits,Minh-Thu Nguyen,Manli Na,Zhicheng Hu,Tao Jin,Mariana Do Nascimento Stroparo,Friedrich Götz,Anders Jarneborn,Anna Karlsson,Pradeep Kumar Kopparapu,Abukar Ali

doi:10.1038/s41598-020-64879-4

Abstract

Permanent joint dysfunction is a devastating complication in patients with septic arthritis. Staphylococcus aureus (S. aureus) lipoproteins (Lpp), the predominant ligands for TLR2, are known to be arthritogenic and induce bone destruction when introduced directly into the joint. Here, we aim to investigate the importance of S. aureus Lpp and TLR2 in a hematogenous septic arthritis model, which is the most common route of infection in humans. C57BL/6 wild-type and TLR2 deficient mice were intravenously inoculated with S. aureus Newman parental strain or its lipoprotein-deficient Δlgt mutant strain. The clinical course of septic arthritis, radiological changes, and serum levels of cytokines and chemokines, were assessed. Newman strain induced more severe and frequent clinical septic polyarthritis compared to its Δlgt mutant in TLR2 deficient mice, but not in wild-type controls. Bone destruction, however, did not differ between groups. Lpp expression was associated with higher mortality, weight loss as well as impaired bacterial clearance in mouse kidneys independent of TLR2. Furthermore, Lpp expression induced increased systemic pro-inflammatory cytokine and neutrophil chemokine release. Staphylococcal Lpp are potent virulence factors in S. aureus systemic infection independent of host TLR2 signalling. However, they have a limited impact on bone erosion in hematogenous staphylococcal septic arthritis.

Highlights

Permanent joint dysfunction is a devastating complication in patients with septic arthritis
To study the importance of S. aureus Lpp and the influence of Toll-like receptor 2 (TLR2) deficiency on the severity and frequency of clinical arthritis, wild-type (WT) and TLR2 deficient (TLR2−/−) mice were intravenously inoculated with an arthritic dose of either S. aureus Newman parental strain expressing Lpp (WT/Newman and TLR2−/−/Newman, respectively) or S. aureus NewmanΔlgt mutant strain (WT/Δlgt and TLR2−/−/Δlgt, respectively)
With regards to the effect of TLR2, we observed that TLR2−/− mice inoculated with the Newman parental strain developed significantly more severe clinical arthritis than the WT mice infected with the same strain (P = 0.02 on day 7, and P = 0.05 on day 10; Fig. 1A), whereas there was no difference when Δlgt mutant strain was used, indicating that TLR2 deficiency aggravates arthritis only in the presence of Lpp

Summary

Introduction

Permanent joint dysfunction is a devastating complication in patients with septic arthritis. Staphylococcal Lpp are potent virulence factors in S. aureus systemic infection independent of host TLR2 signalling They have a limited impact on bone erosion in hematogenous staphylococcal septic arthritis. We demonstrated that purified S. aureus Lpp, when injected intra-articularly into the mouse knee joints, induced destructive arthritis in TLR2-dependent manner[6]. It is well-known that the majority of septic arthritis in patients is caused by hematogenous spreading of bacteria[11]. We investigated the role of staphylococcal Lpp as well as TLR2 in our well-established hematogenous mouse model of S. aureus-induced septic arthritis. Our findings demonstrate that expression of staphylococcal Lpp increases the virulence of S. aureus systemic infection, independently of TLR2, but their effect on radiological bone erosion is limited

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