Staphylococcus aureus is a commensal organism that colonizes the skin, nasal passages, and other body sites of approximately 30% of the human population [1] but can shift to cause invasive infections in nearly every tissue, including the heart, skin and soft tissue, bloodstream, lung, and bone, as well as medical implants [2]. The duality of S. aureus as a commensal and pathogen underscores its metabolic flexibility and ability to evade immune defenses [3]. A key factor in S. aureus persistence is the ability to form biofilm, where bacteria transition from an individual (planktonic) state, typically associated with acute infections, to a highly organized and resilient biofilm community, which is linked to chronic disease [4].

S. aureus strains exhibit diversity in their ability to form biofilm [5]. For example, a study evaluating 76 methicillin-resistant S. aureus (MRSA) isolates from different clonal lineages found that only 16 were capable of consistently forming robust biofilms [6]. Table 1 summarizes some S. aureus strains commonly used for in vivo biofilm studies, highlighting their key characteristics. Our prior work in a mouse model of prosthetic joint infection (PJI) demonstrated that three distinct S. aureus strains, LAC, MW2, and UAMS-1, elicited similar leukocyte infiltrates and inflammatory mediator production with roughly equivalent biofilm titers [7]. This suggests that although S. aureus isolates can exhibit diverse phenotypes during planktonic infections (i.e. sepsis, pneumonia, skin and soft tissue infection) [2], these inherent strain differences appear less critical in affecting biofilm outcomes. However, additional studies comparing S. aureus isolates in other biofilm models are warranted to support this possibility.

Immunometabolism, the intersection of immune function and metabolism, plays a pivotal role in determining how the host responds to biofilm infections [8]. Immune cells, including macrophages (MΦs) and neutrophils (PMNs), undergo metabolic reprogramming to meet the increased energy demands of infection and inflammation. However, during chronic infections, such as those caused by S. aureus biofilms, these metabolic pathways can become dysregulated, leading to impaired immune function and biofilm persistence 3, 9. This review explores the immunometabolic landscape of S. aureus biofilm infections, with a focus on two clinically relevant models, namely, craniotomy and PJI (Figure 1), highlighting metabolic variations in immune responses across distinct biofilm niches caused by the same pathogen [10]. This information is critical to understand how tissue-specific metabolic adaptations contribute to the chronicity of biofilm infections. In some instances, metabolic programming in response to other bacterial pathogens is discussed when information about S. aureus biofilm is lacking.