University of Rochester Medicine researchers have identified a protein associated with some of the most severe bone and joint infections, a finding that could eventually help doctors predict which patients are at greatest risk for complications and open the door to new treatment strategies.
The research centers on a T cell protein known as TIM-3, which investigators found at elevated levels in severe chronic infections caused by Staphylococcus aureus, or S. aureus. The bacterium is a common cause of bone infections that can develop after orthopedic surgery or joint replacement.
The study, published in Nature Communications Medicine, examined humanized mice and patient bone samples. Researchers found that during chronic S. aureus infection, T cells can become dysfunctional and express high levels of immune checkpoint proteins, including TIM-3.
Those proteins effectively act as brakes on the immune system, limiting the ability of T cells to respond to infection.
Gowrishankar Muthukrishnan, an assistant professor of orthopaedics and microbiology and immunology at the University of Rochester, said the findings suggest T cells in persistent bone infections can become exhausted in a way similar to what has been observed in cancer and some viral infections.
“Our research shows that T cells respond similarly in bone infection but also experience exhaustion due to constant antigenic stimulation from bacteria, which prevents them from performing their intended immune functions effectively,” Muthukrishnan said.
Researchers also found that high TIM-3 levels in patient serum were associated with worse clinical outcomes. Muthukrishnan said immune checkpoint protein levels were able to predict patient outcomes with 90% accuracy in the study.
That raises the possibility of using TIM-3 and related proteins as biomarkers to help surgeons determine whether a patient is more likely to need aggressive treatment or could be managed more conservatively.
A future blood test could potentially provide doctors with another tool for judging the severity of an infection before complications become more difficult to control.
Bone and joint infections can be particularly difficult to treat when bacteria become established around an artificial joint or inside bone. While infections following elective orthopedic surgery occur in a relatively small percentage of cases, researchers said reinfection or relapse rates can reach 30%.
Treatment costs can reach $150,000 per patient.
In some cases, antibiotics are enough to eliminate the infection. In others, patients may need repeated surgeries, removal of an infected implant or, in the most serious circumstances, amputation to prevent a life-threatening infection from spreading.
Researchers said about 13% of patients infected with S. aureus become septic and die from multiorgan failure. Chronic S. aureus osteomyelitis can also require prolonged antibiotic treatment and repeated revision surgeries.
Cancer drugs could point toward new treatment
The findings could also have implications beyond diagnosis.
Researchers are now exploring whether drugs already used to boost T cell activity in cancer patients could be repurposed to help patients fight chronic bacterial bone infections.
Katya McDonald, a Ph.D. candidate and co-first author of the study, said drugs that target immune checkpoint proteins could potentially be used alongside antibiotics to strengthen the immune response.
“If we know TIM-3 is on T cells in bone infection, we may be able to leverage these drugs to suppress it,” McDonald said. “While physicians will continue to use antibiotics, these cancer drugs could be used in conjunction to help boost the immune system response to the infection.”
That approach remains experimental. Researchers have not established that checkpoint-blocking cancer drugs are safe or effective for treating bone infections, and more study is needed before such treatments could become part of routine care.
Muthukrishnan has received a $2.7 million National Institutes of Health grant to continue studying diagnostic and treatment options for implant-associated bone infections.
As part of that work, his team will evaluate patients based on their T cell exhaustion profiles and test whether immune checkpoint blockade drugs can restore T cell function in chronic infections.
Researchers will also work with orthopedic surgeons to collect bone marrow samples during revision surgeries and further examine patterns of T cell exhaustion.
The long-term goal is to develop a serum test that could help physicians determine how aggressively to treat an infection and whether existing FDA-approved immune checkpoint drugs could eventually have a role in treating bone infections.
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