Targeting Macrophage Activation for the Prevention and Treatment of Staphylococcus aureus Biofilm Infections

Biofilm infections often lead to significant morbidity due to their chronicity and recalcitrance to antibiotics. We have demonstrated that methicillin-resistant Staphylococcus aureus (MRSA) biofilms can evade macrophage (M Phi) antibacterial effector mechanisms by skewing M Phi s toward an alternatively activated M2 phenotype. To overcome this immune evasion, we have used two complementary approaches. In the first, a proinflammatory milieu was elicited by local administration of classically activated M1 M Phi s and in the second by treatment with the C5a receptor (CD88) agonist EP67, which invokes M Phi proinflammatory activity. Early administration of M1-activated M Phi s or EP67 significantly attenuated biofilm formation in a mouse model of MRSA catheter-associated infection. Several proinflammatory mediators were significantly elevated in biofilm-infected tissues from M Phi- and EP67-treated animals, revealing effective reprogramming of the biofilm environment to a proinflammatory milieu. A requirement for M Phi proinflammatory activity was demonstrated by the fact that transfer of MyD88-deficient M Phi s had minimal impact on biofilm growth. Likewise, neutrophil administration had no effect on biofilm formation. Treatment of established biofilm infections with M1-activated M Phi s also significantly reduced catheter-associated biofilm burdens compared with antibiotic treatment. Collectively, these results demonstrate that targeting M Phi proinflammatory activity can overcome the local immune inhibitory environment created during biofilm infections and represents a novel therapeutic strategy. The Journal of Immunology, 2013, 190: 2159-2168.