Abstract
Staphylococcus aureus prosthetic joint infections (PJIs) are broadly considered incurable, and clinical diagnostics that guide conservative vs. aggressive surgical treatments don't exist. Multi-omics studies in a humanized NSG-SGM3 BLT mouse model demonstrate human T cells: 1) are remarkably heterogenous in gene expression and numbers, and 2) exist as a mixed population of activated, progenitor-exhausted, and terminally-exhausted Th1/Th17 cells with increased expression of immune checkpoint proteins (LAG3, TIM-3). Importantly, 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-γ, IL-2, TNF-α, IL-17) revealed that TIM-3 was highly predictive of adverse disease outcomes (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 blockade of checkpoint proteins could potentially improve outcomes following surgery.