Microorganisms can interact with the local mesenchyme and induce a tissue-specific response that damages bone tissue by altering homeostasis. The disturbance of bone homeostasis can be caused by a direct interaction of bacteria with mesenchymal cells such as osteoblasts, osteocytes and fibroblasts and through subsequent induction of the inflammatory host response. Clinically, treatment to eradicate infection is impaired by specific pathogen properties, such as dormant phenotypes, that limit the therapeutic action of antimicrobials. Further, it is not known what role the local metabolic environment plays in facilitating bacterial persistence and inducing an excessive host immune response that enhances tissue damage. Patients can recover rapidly from acute infections but mostly they develop chronic and persistent bone diseases, which are difficult to treat, are detrimental on the functional outcome and subsequently cause a large socioeconomic burden due to prolonged use of antibiotics, long hospitalization and the costs for additional surgical interventions. Therefore, our proposal aims to identify key pathways that allow pathogens to persist and localize therapeutic targets within the mesenchyme that could be used to address this public health problem. Using Staphylococcus aureus (S. aureus), the most common causative pathogen of osteomyelitis, and Porphyromonas gingivalis(P. gingivalis), a main pathogen involved in periodontal disease, as model systems for bacterial-associated bone loss, we will investigate specific mechanisms underlying bacterial persistence and target mesenchymal immune modulation. For this purpose, we will use fatty acids that are important lipid-metabolic fuels as targets to examine novel immune modulatory dietary strategies in bacterial-induced bone loss. Palmitic (PA) and oleic acid (OA), the most abundant saturated and monounsaturated fatty acids in the Western diet and in serum, display distinguish immune modulatory properties depending on their saturation and can be a dietary target. The main objective is to target bone-pathogen interactions as well as modulate immune-metabolic host factors.