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

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.