University of Rochester Medical Center researchers have identified a protein associated with the most severe bone infections, a finding that could help physicians predict which patients face poor outcomes and guide work on immune-based treatments.
The team found that T cells in chronic Staphylococcus aureus infections became dysfunctional and expressed high levels of the immune checkpoint protein TIM-3. Higher TIM-3 levels in patient serum were associated with worse clinical outcomes, according to a study in Nature Communications Medicine.
Protein could become a clinical warning sign
Researchers studied humanized mice and bone samples from patients. They found that constant exposure to bacterial antigens appeared to exhaust T cells in a pattern similar to dysfunction observed in cancer and viral infections.
Gowrishankar Muthukrishnan, an assistant professor of orthopedics, microbiology and immunology, said serum immune-checkpoint levels predicted patient outcomes with 90% accuracy in the study. A reliable biomarker could help surgeons decide whether a joint infection requires aggressive treatment or a more conservative approach.
Bone and joint infections most often follow surgery to repair a bone or implant an artificial joint and are commonly caused by S. aureus. About 2 million joint replacements are performed worldwide each year, the researchers said.
Infections occur after an estimated 1% to 5% of elective orthopedic procedures, but relapse or reinfection rates can reach 30%. Treatment can cost as much as $150,000 per patient.
Severe cases may require implant removal, repeated revision surgery, prolonged antibiotics or amputation. Researchers said about 13% of patients infected with S. aureus become septic and die from multiorgan failure.
Clinicians currently lack a dependable test for forecasting which infections will persist, and no approved immunotherapy is available when antibiotics fail. That uncertainty can make early decisions about surgery and the intensity of treatment especially difficult.
Existing cancer drugs offer a research path
Immune checkpoint proteins act as brakes on the immune response. The team is studying whether drugs that block those proteins and boost T-cell performance in cancer could be used alongside antibiotics for chronic bacterial infections.
Doctoral candidate Katya McDonald said the drugs could potentially suppress TIM-3 and help the immune system respond more effectively. The work does not establish such treatment as safe or effective for bone infection, and the researchers described it as a future testing path rather than current clinical guidance.
Muthukrishnan received a $2.7 million National Institutes of Health grant to study diagnostic and treatment options for implant-associated bone infection. His laboratory will assess patients by T-cell exhaustion profiles and test checkpoint-blockade drugs in chronic infection models.
The project includes collaboration with orthopedic surgeons who will collect bone marrow during revision procedures. The team ultimately hopes to develop a serum test and determine whether any FDA-approved checkpoint drugs could become part of standard infection care.
The research also received support from the AOTrauma Clinical Priority Program, an immunology fellowship program and internal University of Rochester grants. Collaborators included scientists at Cornell University, the University of Wisconsin, Virginia Commonwealth University and research institutions in Mexico.
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