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.