Beyond the skin barrier: commensal S. epidermidis imprint systemic immunity to invasive biofilm infection.

Staphylococcus epidermidis, a dominant human skin commensal that promotes microbial homeostasis from early life, can transition to an opportunistic pathogen under certain conditions, including invasive, biofilm-associated infections linked to medical devices. Neonatal exposure to skin commensals induces a lifelong immunological imprint in the skin, characterized by immunoregulatory responses. We therefore hypothesized that early life exposure to S. epidermidis influences immune responses to invasive biofilm-associated infections later in life. Using a murine model of biofilm-related S. epidermidis bone infection induced in adulthood, we show that mice previously colonized as neonates displayed substantially different immune responses to later-life invasive infection than those not colonized or those colonized as adults. Neonatal colonization led to greater numbers of NK cells and neutrophils than no colonization, along with reduced Tregs and Th1 cells, and consistent increase in immune checkpoint receptor PD-1(+) Tregs, T effector, Th1 and Th2 cells across infected bone marrow, blood and spleen. These PD-1-related immune modulations were absent in the adult-colonized group, which had the highest numbers of Tregs, Th1 and Th2 cells of all three groups. These findings reveal that early exposure to commensal bacteria strongly impacts the response to invasive infection later in life. Notably, the response depends on the timing of previous exposure. Neonatal colonization drives T cell modulation, resembling neonatal immunity, while adult-colonization increases specific T cell abundance. These differences highlight the essential role of skin commensal colonization in shaping the quality of pathogen immunity to protect against invasive, biofilm-associated infection later in life.