Regulation of Staphylococcus aureus Infection of Macrophages by CD44, Reactive Oxygen Species, and Acid Sphingomyelinase

Aims: Staphylococcus aureus plays an important role in sepsis, pneumonia, and wound infections. Acid sphingomyelinase (Asm)-deficient mice are highly susceptible to pulmonary S. aureus infections. Here, we investigated the role of CD44 as a molecule that mediates important aspects of the infection of macrophages with S. aureus. Results: We showed that CD44 activation by S. aureus stimulated Asm via the formation of reactive oxygen species, resulting in ceramide release, clustering of CD44 in ceramide-enriched membrane platforms, CD44/Asm-dependent activation of Rho family GTPases, translocation of phospho-ezrin/radixin/moesin to the plasma-membrane, and a rapid rearrangement of the actin cytoskeleton with cortical actin polymerization. Genetic deficiency of CD44 or Asm abrogated these signaling events and thereby reduced internalization of S. aureus into macrophages by 60-80%. Asm-deficient macrophages also exhibited reduced fusion of phagosomes with lysosomes, which prevented intracellular killing of S. aureus in macrophages and thereby allowed internalized S. aureus to replicate and cause severe pneumonia. Innovation and Conclusion: The CD44-Asm-ceramide system plays an important role in the infection of macrophages with S. aureus. Antioxid. Redox Signal. 28, 916-934.