Immune Checkpoint Molecules as Biomarkers of Staphylococcus aureus Bone Infection and Clinical Outcome
Saito, M.; McDonald, K. A.; Grier, A. K.; Meghwani, H.; Rangel-Moreno, J.; Becerril-Villanueva, E.; Gamboa-Dominguez, A.; Bruno, J.; Beck, C. A.; Proctor, R. A.; Kates, S. L.; Schwarz, E. M.; Muthukrishnan, G.
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Staphylococcus aureus prosthetic joint infections (PJIs) are broadly considered incurable, and clinical diagnostics that guide conservative vs. aggressive surgical treatments dont 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-{gamma}, IL-2, TNF-, 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.
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