Significance
Staphylococcus aureus (SA) is the leading cause of skin and skin structure infections (SSSI), which are the main portal of entry for life-threatening invasive infections. Treatment failures are increasingly common due to antibiotic resistance. Importantly, SA SSSI exhibit high 1-year recurrence, despite high antibody levels against staphylococcal antigens. Therefore, critical determinants of immune protection against recurrent SA SSSI are not well understood. The present study offers important insights in this area, including: ( i ) macrophages can confer protective memory transferrable to naïve hosts; ( ii ) SA SSSI can induce memory in bone marrow myeloid precursors; and ( iii ) specific memory against recurring SA SSSI is localized and distinct from disseminated infection. These findings will accelerate novel strategies to prevent and treat SA infections.