Bone and joint infections (BJI)

J. Josse, MCU-HDR / F. Laurent, PU-PH, in close collaboration with P. Verhoeven, PU-PH-GIMAP

Staphylococci are a leading cause of BJI, a major public health concern. Our aim is to decipher the host-pathogen interactions that drive chronic infections, in particular the ability of staphylococci to survive and replicate within host cells in the periprosthetic bone environment.

Using innovative tools (e.g.,  CRISPR/Cas9-based genome editing, primary cell-based  organoids, live-cell confocal microscopy, etc.). Our focus is on the molecular mechanisms involved in:

• Cell invasion (both cellular and bacterial sides)
• S. aureus-containing vacuole damage (e.g., intracellular toxin expression and regulation, vacuole composition)
• S. aureus intracellular replication (starvation response, iron scavenging strategies and nutrient access)
• S. aureus persister formation (i.e. stringent response) triggered by the harsh intracellular environment (e.g., low pH, oxidative stress…) and the antimicrobial exposure
• Impact of autophagic fluxes on intracellular staphylococci

Fig. 1. Intracellular fate of S. aureus: To invade bone and enter osteoblasts, S. aureus exploits BEM components like fibronectin as a bridge, using its FnBPs and the osteoblast's α5β1 integrin to facilitate internalization. After internalization into osteoblasts, S. aureus resides within an endosome, where it can either be killed, survive, or escape. The bacterium can secrete various toxins, including pore-forming toxins like PSMs, which facilitate phagosomal escape and host cell death. Upon escaping to the cytosol, S. aureus can rapidly replicate and induce host cell death, or persist intracellularly, evading the immune system. No or less virulent bacteria can survive persistently within host cells by reducing cytotoxicity. In the cytosol, S. aureus depletes nutrients, inducing autophagy, which it can manipulate for protection and replication. Intracellular stress can trigger the formation of SCVs contributing to chronic infections. SCVs can persist within various bone cells, including osteoblasts, and osteocytes, serving as potential reservoirs. Collet, Q., et al., Bone