Novel Insights into Staphylococcus aureus Deep Bone Infections: the Involvement of Osteocytes

Abstract

Periprosthetic joint infection (PJI) is a potentially devastating complication of orthopedic joint replacement surgery. PJI with associated osteomyelitis is particularly problematic and difficult to cure. Whether viable osteocytes, the predominant cell type in mineralized bone tissue, have a role in these infections is not clear, although their involvement might contribute to the difficulty in detecting and clearing PJI. Here, using Staphylococcus aureus, the most common pathogen in PJI, we demonstrate intracellular infection of human-osteocyte-like cells in vitro and S. aureus adaptation by forming quasi-dormant small-colony variants (SCVs). Consistent patterns of host gene expression were observed between in vitro-infected osteocyte-like cultures, an ex vivo human bone infection model, and bone samples obtained from PJI patients. Finally, we confirm S. aureus infection of osteocytes in clinical cases of PJI. Our findings are consistent with osteocyte infection being a feature of human PJI and suggest that this cell type may provide a reservoir for silent or persistent infection. We suggest that elucidating the molecular/cellular mechanism(s) of osteocyte-bacterium interactions will contribute to better understanding of PJI and osteomyelitis, improved pathogen detection, and treatment.

The role of bacterial stimuli in inflammation-driven bone formation

“…This was a significant finding, since it is often presumed that periosteum-derived cells are essential for inflammation-induced new bone formation in the long bones (Alexander et al, 2017;Lin et al, 2014). The observations in the ectopic location furthermore indicated that pro-osteogenic effects of killed bacteria cannot be attributed to the specific immune reaction mediated by boneresiding osteoblasts or osteocytes in response to bacteria (Gasper et al, 2002;Yang et al, 2018). The ectopic location lacks the osteogenic and osteoinductive stimuli that are normally present in bone (Albrektsson and Johansson, 2001).…”

2018 International Consensus Meeting on Musculoskeletal Infection: Research Priorities from the General Assembly Questions

“…It was also clear from the robust and passionate discussion at the ICM 2018, that the time has come to address the need for a scientifically and clinically functional definitions for: “acute versus chronic” infection (https://www.ors.org/wp-content/uploads/2019/01/Question-1.pdf), “implant colonization versus implant‐related infection” (https://www.ors.org/wp-content/uploads/2019/01/Question-2.pdf), and “persistent wound drainage” (https://www.ors.org/wp-content/uploads/2019/01/Question-3.pdf). These new definitions must incorporate our current understanding that the management of bone and implant‐related infections is inextricably intertwined with the biology of biofilms, infection of osteoblasts and osteocytes, and invasion of the osteocytic‐canalicular network by the bacteria . Thus, the challenge to define treatment protocols is dependent on defining biologic metrics, such as when persister cells become inaccessible to phagocytes, and when antimicrobial levels (and durations) needed to eradicate persister cells are not achievable systemically (minimum biofilm eradication concentration [MBEC]), as discussed by the https://www.ors.org/icm-2018-biofilm-workgroup/ .…”

Anin vitrobiofilm model ofStaphylococcus aureusinfection of bone

“…Furthermore, known to survive in osteoblasts and osteocytes (Yang et al . ), SCVs have the potential to persist even when bone is being remodelled and reformed. Three‐dimensional scaffolds which allow bone generation alongside sustained release of antibiotic are under development (Cicuéndez et al .…”