Graduate Research Asssitant University of Nebraska Medical Center, United States
Disclosure(s):
Adedayo Ogunware, M.Sc.: No financial relationships to disclose
Introduction/Rationale: Neurosurgical procedures such as craniotomies carry up to a 15% infection risk, predominantly due to Staphylococcus aureus (S. aureus) biofilms. These biofilms resist antibiotics and promote immune suppression, enabling chronic infection. Granulocytic myeloid-derived suppressor cells (G-MDSCs) emerge as key mediators of this immunosuppression, but the mechanisms driving their development, presumably from neutrophils, remain poorly defined.
Methods: We exposed bone marrow-derived neutrophils to S. aureus biofilm and analyzed phenotypic and functional changes via flow cytometry, RNA- sequencing, and T cell suppression assays. Genetic knockout models lacking Toll-like receptor 2 (TLR2) or MyD88 were used to delineate host signaling pathways. Additionally, we screened the S. aureus Nebraska Transposon Mutant Library (NTML) to identify bacterial factors responsible for neutrophil reprogramming.
Results: Exposure to S. aureus biofilm transformed neutrophils into G-MDSC-like cells, exhibiting elevated CD11b, CD14, and PD-L1 expression, reduced bactericidal capacity, and suppression of T cell proliferation. TLR2-deficient neutrophils showed markedly reduced acquisition of these traits, while MyD88 deletion completely prevented the shift, implicating MyD88-dependent pathways. NTML screening identified specific bacterial TLR2 ligands as essential for driving this reprogramming.
Conclusion: Our findings reveal that S. aureus biofilms exploit TLR2-MyD88 signaling to reprogram neutrophils into immunosuppressive G-MDSC-like cells. This host-pathogen interaction underlies biofilm persistence and highlights both bacterial-derived TLR2 ligands and host TLR2 signaling as promising therapeutic targets to restore antimicrobial immunity in neurosurgical infections.
