Immune Checkpoint Molecules as Biomarkers of Outcomes in Staphylococcus aureus Bone Infections

ABSTRACT: Staphylococcus aureus prosthetic joint infections (PJIs) are considered incurable. Unfortunately, clinical diagnostics to guide conservative vs. aggressive surgical treatment of PJI patients are not evidence-based. Developing clinical biomarkers are crucial for defining immunopathogenesis of PJIs. PJI in humanized mice is characterized by increased infection, bone osteolysis, and large numbers of proliferating CD3+/Tbet+ cells adjacent to purulent abscesses in the bone marrow. Multi-omics studies in a humanized NSG-SGM3 BLT PJI mouse indicated the role of human T cells where 1) human T cells are remarkably heterogenous in gene expression and numbers, 2) human Th1/Th17 exists as a mixed population of activated, progenitor-exhausted, and terminally-exhausted cells which exhibit increased expression of immune checkpoint proteins (LAG3, TIM-3) 2-weeks post-infection. Moreover, these proteins are upregulated in the serum and the bone marrow of S. aureus PJI patients. A multiparametric nomogram combining high serum immune checkpoint protein levels with low proinflammatory cytokine levels (IFN-g, IL-2, TNF-α, IL-17) revealed that TIM-3 was highly predictive of adverse outcomes in PJI patients (AUC=0.89). Hence, T cell impairment in the form of immune checkpoint expression and exhaustion could be a functional biomarker for S. aureus PJI disease outcome, and checkpoint blockade may benefit PJI patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269658 | GEO | 2026/06/30

REPOSITORIES: GEO