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Bone infection, while relatively rare, can be debilitating and potentially fatal. In recent years, researchers in the Center for Musculoskeletal Research at the University of Rochester Medical Center have made several discoveries that position them to advance new treatments and possible cures for bone infections. Now, a nearly $6 million, 5 year award from the National Institute of Arthritis and Musculoskeletal and Skin Disease at the National Institutes of Health, will allow the group to create a new multidisciplinary research program devoted to studying bone infections.

The CMSR has been among the top five NIH-funded orthopaedic research centers in the nation for over ten years, and Edward Schwarz, Ph.D., Burton Professor of Orthopaedics and director of the CMSR, has been the top NIH-funded orthopaedic researcher in the nation three years running. This new grant, awarded to Schwarz and throng of researchers from across the University of Rochester and beyond, brings the center's total forecasted earnings for 2017 to $28 million.

Of the millions of Americans who have joint replacement surgeries each year, less than five percent come away with an infection. But this minority of patients must endure a long and difficult road to recovery, if they recover at all. The vast majority of these infections are caused by a bacteria called Staphylococcus aureus, including the dreaded methicillin-resistant strain (MRSA), which causes sepsis and death in 13 percent of infected patients.

Patients who survive these infections face multiple surgeries to remove infected tissue, months of strong antibiotic treatments, and a high likelihood of re-infection. For a long time, researchers have been working to understand how this bacteria evades treatment and Schwarz believes he has figured out.

Together with Karen Bentley, director of the Electron Microscopy Core at URMC, Schwarz showed that the bacteria can crawl deep into tiny channels in bones, possibly taking shelter there and later emerging to re-establish an infection. Though S. aureus was originally thought to be incapable of movement, Bentley and Schwarz, in collaboration with James McGrath, Ph.D., professor of Biomedical Engineering at URMC, and his spin-off company, SiMPore Inc., showed that this bacteria can migrate through tiny pores in membranes in the lab.

This new grant will allow Schwarz and Hani A. Awad, Ph.D., professor of Biomedical Engineering and Orthopaedics in the CMSR, to investigate exactly how S. aureus gets into bone and develop new treatments that target those mechanisms. Microbiologists Steven Gill, Ph.D., and Paul Dunman, Ph.D., in the Department of Microbiology and Immunology, will help the team develop new antibiotics to inhibit bone infection, which will be 3D printed into spacers that replace infected joint implants. Delivering the antibiotic at the site of infection may save patients' limbs and lives.

Schwarz has also been working to understand what makes certain patients more susceptible to S. aureus infections than others, including why some patients recover relatively easily, while others die.

"Death following surgical site infection is not random," said Schwarz. "By studying patient immune responses to this bacteria, we might be able to predict who will be fine and who will need extra medical attention."

S. aureus can also become resistant to antibiotics, making it extremely deadly and difficult to eradicate. Better understanding patients' immune reactions to the bacteria may provide new approaches to defeating it.

In an international study of more than 300 patients with infected total joint replacements, Schwarz and his team including John Daiss, Ph.D., and Chao Xie, M.D., in the CMSR, found that patients fared well if their immune systems attacked a certain S. aureus protein, and poorly if they attacked another. Patients who produced antibodies attacking autolysin, a protein important for cell division, were protected. Those who produced antibodies against a family of iron sensing determinant (Isd) proteins, which help S. aureus sap nutrients from its host, were more likely to experience sepsis and even die.

It is unclear why antibodies that attack Isd proteins are bad for patients, and Schwarz is determined to use this new funding to figure it out. He will also analyze the full complement of antibodies produced by patients infected with several types of staph bacteria to see if there are more good- and bad-cop antibodies that could help inform new treatments.

The Clinical Research Core of this program will be run by Stephen L. Kates, M.D., at Virginia Commonwealth University.