Interactions between Macrophages and Biofilm during <i>Staphylococcus aureus</i>-Associated Implant Infection: Difficulties and Solutions

Abstract

Staphylococcus aureus (S. aureus) biofilm is the major cause of failure of implant infection treatment that results in heavy social and economic burden on individuals, families, and communities. Planktonic S. aureus attaches to medical implant surfaces where it proliferates and is wrapped by extracellular polymeric substances (EPS), forming a solid and complex biofilm. This provides a stable environment for bacterial growth, infection maintenance, and diffusion, and protects the bacteria from antimicrobial agents and the immune system of the host. Macrophages are an important component of the innate immune system, and resist pathogen invasion and infection through phagocytosis, antigen presentation, and cytokine secretion. The persistence, spread, or clearance of infection is determined by interplay between macrophages and S. aureus in the implant infection microenvironment. In this review, we discuss the interactions between S. aureus biofilm and macrophages, including the effects of biofilm-related bacteria on the macrophage immune response, roles of myeloid-derived suppressor cells during biofilm infection, regulation of immune cell metabolic patterns by the biofilm environment, and immune evasion strategies adopted by the biofilm against macrophages. Finally, we summarize the current methods that support macrophage mediated removal of biofilms and emphasize the importance of considering multi-dimensions and factors related to implant associated infection such as immunity, metabolism, the host, and the pathogen when developing new treatments.

Comparative evaluation of small molecules reported to be inhibitors of Staphylococcus aureus biofilm formation

“…Many recent reviews have emphasized the need for such inhibitors, discussed alternative strategies, and summarized compounds investigated in this context in diverse bacterial species ( 2 , 3 , 39 – 41 ). We have focused our efforts on S. aureus owing to its prominence as a cause of orthopedic infections including those involving bone and indwelling hardware, both of which are characterized to a significant extent by the formation of a biofilm ( 42 – 48 ). Biofilm formation and maintenance of the biofilm lifestyle in S. aureus are dynamic and complex processes influenced by many regulatory loci, but our studies have led us to focus on sarA because the mutation of sarA limits biofilm formation to a greater extent than mutation of any other regulatory locus we have examined, and it does so in diverse clinical isolates including methicillin-susceptible and methicillin-resistant strains ( 11 – 16 , 18 , 19 , 34 , 35 , 49 – 51 ).…”

The Staphylococcus aureus ArlS Kinase Inhibitor Tilmicosin Has Potent Anti-Biofilm Activity in Both Static and Flow Conditions

“…pCM29 is used to build a promoter-GFP reporter system. pRB475 and pCN51 are used to construct arlRS complementation plasmids pCN- arlRS and pRB- arlRS [ 58 , 59 ]. The temperature-sensitive plasmid pKOR1 is used for gene knockout in staphylococci [ 60 ].…”

Metabolism Shapes Immune Responses to <i>Staphylococcus aureus</i>

“…Another enigma that remains to be understood relates to the dichotomy in infectious outcomes between S. aureus planktonic versus biofilm infection when proinflammatory cytokine expression is a hallmark of both. In the case of planktonic S. aureus infection, this response is typically linked to bacterial clearance [ 110 , 111 ]. However, proinflammatory mediators are also produced during biofilm infection and although they have been shown to play a role in preventing S. aureus outgrowth [ 112 – 115 ], infection persists.…”