Immunoplasticity: A Key Determinant in the Outcome of Neurosurgical Biofilm Infection

A craniotomy involves the temporary removal of a piece of the skull, providing access to the intracranial compartment for numerous indications including the excision of brain tumors, implantation of medical devices, or evacuation of hematomas. In a minority of cases (~1-5%), post-surgical infection develops, which is most commonly caused by Staphylococcus aureus, which forms a biofilm on the skull and resists antibiotic- and immune-mediated clearance. Current management of craniotomy infection involves additional surgical procedures to remove the biofilm nidus and chronic antibiotic therapy to prevent recurrence. Given this and rapidly expanding rates of antimicrobial resistance, there is renewed interest in the development of immune-based therapies to treat biofilm infections. This dissertation explores the role of immunoplasticity, the ability of the immune system to adapt to environmental cues present in the biofilm milieu, and chiefly during craniotomy infection. The work encompasses three main themes. First, the effects of tumor necrosis factor (TNF) and interferon-γ (IFN-γ) signaling on shaping immune responses and pathogen abundance during S. aureus craniotomy infection were explored, identifying key roles for each signaling pathway for both leukocyte recruitment and polarization in response to biofilm. Second, both patient samples and a mouse model of craniotomy infection were leveraged to explore immune polarization across the blood-to-tissue transition, tissue compartments, and distinct biofilm models and the kinetics of these specifications. Glycolysis, amino acid, fatty acid, and nucleotide metabolism were identified as key mediators of phenotypic differences in immune responses across time and tissue niche. Third, the role of epigenetics in modulating immune responses during craniotomy infection was explored. This work implicated histone acetylation as a key factor in controlling inflammatory mediator production, both in vitro and in vivo. Global histone deacetylase (HDAC) inhibition during S. aureus craniotomy infection resulted in significantly elevated bacterial burden, indicative of an ineffective immune response. Together, these findings support the existence of metabolic and epigenetic layers of control over the immune response to biofilm infection, aspects that may be leveraged for future immunomodulatory intervention.