Targeting macrophage activation for the prevention and treatment of staphylococcus aureus biofilm infections

Mark L. Hanke, Cortney E. Heim, Amanda Angle, Sam D. Sanderson, Tammy Kielian

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

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 (Mφ) antibacterial effector mechanisms by skewing Mφs 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 Mφs and in the second by treatment with the C5a receptor (CD88) agonist EP67, which invokes Mφ proinflammatory activity. Early administration of M1-activated Mφs or EP67 significantly attenuated biofilm formation in a mouse model of MRSA catheterassociated infection. Several proinflammatory mediators were significantly elevated in biofilm-infected tissues from Mφ- and EP67-treated animals, revealing effective reprogramming of the biofilm environment to a proinflammatory milieu. A requirement for Mφ proinflammatory activity was demonstrated by the fact that transfer of MyD88-deficient Mφs had minimal impact on biofilm growth. Likewise, neutrophil administration had no effect on biofilm formation. Treatment of established biofilm infections with M1-activated Mφs also significantly reduced catheter-associated biofilm burdens compared with antibiotic treatment. Collectively, these results demonstrate that targeting Mφ proinflammatory activity can overcome the local immune inhibitory environment created during biofilm infections and represents a novel therapeutic strategy.

Original languageEnglish (US)
Pages (from-to)2159-2168
Number of pages10
JournalJournal of Immunology
Volume190
Issue number5
DOIs
StatePublished - Mar 1 2013

    Fingerprint

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this