The role of HIF signaling during Staphylococcus aureus osteomyelitis and biomaterial-based treatment strategies

Abstract

Osteomyelitis, inflammation of bone, is highly morbid and is most commonly triggered by Staphylococcus aureus infection. Despite the introduction of antimicrobials, curative treatment of S. aureus osteomyelitis often fails due to intrinsic antimicrobial resistance and immune evasion mechanisms of S. aureus as well as the unique features of infection in bone. It is critical to research the host-pathogen interface during osteomyelitis to develop new treatment strategies. The experiments described in this dissertation investigate the role of hypoxia-inducible factor (HIF) signaling during osteomyelitis and biomaterial-based treatment strategies using in vitro and in vivo models. HIF signaling has previously been identified as the canonical response to hypoxic stress in metazoan cells and regulates thousands of genes. HIF signal is recognized to impact both bone biology and antibacterial immunity. We hypothesized that skeletal cell HIF signaling impacts antibacterial immune responses and bone architecture during S. aureus osteomyelitis. Using genetic models, osteoblast-lineage and myeloid-lineage conditional knockouts of Hif1a or Vhl were generated to model states of low and high HIF signaling. Using these models, it was discovered that 1) conditional knockout of Vhl significantly impacts changes in trabecular bone architecture in divergent ways in osteoblasts versus myeloid cells and 2) conditional knockout of Hif1a does not significantly impact bacterial burdens or bone architecture outcomes during S. aureus osteomyelitis. Investigating potential pharmacologic targets like HIF signaling in the context of infection is important in part due to widespread antimicrobial resistance, which continually drives the need for alternative treatment strategies. With an interest in alternative treatment strategies, poly(propylene sulfide) (PPS)-based nanoparticles were investigated as a drug delivery system for treatment of S. aureus osteomyelitis. PPS nanoparticles were shown to preferentially accumulate at the infected femur. The antivirulence drug, diflunisal, was used as a model drug cargo because it is chemically compatible to load within PPS nanoparticles and has demonstrated efficacy during osteomyelitis following local delivery. Validating efficacy of systemic delivery via PPS nanoparticles, diflunisal-loaded PPS nanoparticles decreased cortical bone destruction compared to vehicle controls. This dissertation concludes with outstanding questions and future directions to further advance these studies.