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

plays an important role in sepsis, pneumonia, and wound infections. Acid sphingomyelinase (Asm)-deficient mice are highly susceptible to pulmonary infections. Here, we investigated the role of CD44 as a molecule that mediates important aspects of the infection of macrophages with . We showed that CD44 activation by 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 into macrophages by 60-80%. Asm-deficient macrophages also exhibited reduced fusion of phagosomes with lysosomes, which prevented intracellular killing of in macrophages and thereby allowed internalized to replicate and cause severe pneumonia. The CD44-Asm-ceramide system plays an important role in the infection of macrophages with . 28, 916-934.