Significance
Up to 30% of methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections fail to resolve despite appropriate therapy. Such infections are persistent and life threatening. Because persistent MRSA isolates are susceptible to antibiotics in vitro, unique interactions among the pathogen, patient, and antibiotic occur in the body that lead to persistent outcomes. To study host factors involved in persistence, we used state-of-the-art methods to explore how genes are modified by methylation in patients who experience persistent vs. resolving MRSA bacteremia. Findings established distinct methylation patterns in these patients, including differential methylation signatures associated with important immune system and related genes. These results may enable approaches to identify and treat patients prone to persistent infection to improve therapeutic outcomes and save lives.