CCR2 contributes to host defense against Staphylococcus aureus orthopedic implant‐associated infections in mice

Abstract

C‐C motif chemokine receptor 2 (CCR2) is an important mediator of myeloid cell chemotaxis during inflammation and infection. Myeloid cells such as monocytes, macrophages, and neutrophils contribute to host defense during orthopedic implant‐associated infections (OIAI), but whether CCR2‐mediated chemotaxis is involved remains unclear. Therefore, a Staphylococcus aureus OIAI model was performed by surgically placing an orthopedic‐grade titanium implant and inoculating a bioluminescent S. aureus strain in knee joints of wildtype (wt) and CCR2‐deficient mice. In vivo bioluminescent signals significantly increased in CCR2‐deficient mice compared with wt mice at later time points (Days 14–28), which was confirmed with ex vivo colony‐forming unit enumeration. S. aureus γ‐hemolysin utilizes CCR2 to induce host cell lysis. However, there were no differences in bacterial burden when the OIAI model was performed with a parental versus a mutant γ‐hemolysin‐deficient S. aureus strain, indicating that the protection was mediated by the host cell function of CCR2 rather than γ‐hemolysin virulence. Although CCR2‐deficient and wt mice had similar cellular infiltrates in the infected joint tissue, CCR2‐deficient mice had reduced myeloid cells and γδ T cells in the draining lymph nodes. Taken together, CCR2 contributed to host defense at later time points during an OIAI by increasing immune cell infiltrates in the draining lymph nodes, which likely contained the infection and prevented invasive spread.

2023 International Consensus Meeting on musculoskeletal infection: Summary from the treatment workgroup and consensus on treatment in preclinical models

“…As a result, this was a controversial question among the delegates with only 69% in agreement, 18% disagreement, and 12.5% abstaining. Typical animal models use a 2‐ to 3‐log 10 reduction in bacterial burden with thresholds below 10 3 –10 4 CFU to define “successful” treatment of underlying infection in experimental settings, and the thresholds of bacterial burden necessary to generate infection appear to be in a similar range 29–33 . Unfortunately, whether these findings directly translate to human infection is not clear.…”

“…| 507 thresholds below 10 3 -10 4 CFU to define "successful" treatment of underlying infection in experimental settings, and the thresholds of bacterial burden necessary to generate infection appear to be in a similar range. [29][30][31][32][33] Unfortunately, whether these findings directly translate to human infection is not clear. Some of the controversy lies in the lack of data regarding bacterial burden in human infection as it resolves with treatment.…”

Dry and liquid formulations of IBT-V02, a novel multi-component toxoid vaccine, are effective against Staphylococcus aureus isolates from low-to-middle income countries

“…For mouse infections with USA300 (SF8300) and LMIC isolates (KCO075, Pyo603, or Gaza209) and for rabbit infections with USA300 (SF8300), S. aureus strains were cultured in tryptic soy broth (TSB) as previously described ( 21 , 22 ). Briefly, S. aureus was streaked onto a tryptic soy agar (TSA) plate (TSB plus 1.5% bacto agar (BD Biosciences)) and grown overnight at 37°C in a bacterial incubator.…”

What’s New in Musculoskeletal Infection

“…On the host side, CCR2 (C-C motif chemokine receptor 2) mediates chemotaxis for macrophages and neutrophils during inflammatory responses. In a murine model of orthopaedic implant-associated infection, CCR2-deficient mice were found to have significantly reduced myeloid inflammatory cells in draining lymph nodes compared with the control wild-type mice 60 . In a study evaluating the ability of orthopaedic infections to co-opt our own immune regulatory system for survival benefits, as malignancies also often do, Warren et al analyzed periprosthetic tissue from patients undergoing revision hip or knee arthroplasty for immune checkpoints related to apoptosis (PD-1 [programmed cell death-1] and its ligand PD-L1).…”