Cao Li1, Yuqing Wu1, Andrea Riehle1, Véronique Orian-Rousseau2, Yang Zhang3, Erich Gulbins1,4, Heike Grassmé1. 1. Department of Molecular Biology, University of Duisburg-Essen, University Hospital, Essen, Germany. 2. Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany. 3. Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas. 4. Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
Abstract
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.
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.
Authors: Björn Fahsel; Hannes Kemper; Joelina Mayeres; Katrin Anne Becker; Cao Li; Barbara Wilker; Simone Keitsch; Matthias Soddemann; Carolin Sehl; Marcus Kohnen; Michael J Edwards; Heike Grassmé; Charles C Caldwell; Aaron Seitz; Martin Fraunholz; Erich Gulbins Journal: Infect Immun Date: 2017-12-19 Impact factor: 3.441