| Streptococcus pneumoniae (the pneumococcus) colonizes the human upper respiratory tract in the presence of many different antimicrobial substances. One of the most abundant antimicrobials on the mucosal surface is lysozyme, which is secreted from the epithelium and also expressed within professional phagocytes. Lysozyme hydrolyzes the peptidoglycan backbone, which leads to lysis of bacterial cells. S. pneumoniae is naturally lysozyme resistant, which has been attributed to two peptidoglycan modifications: deacetylation by PgdA and acetylation by Adr. Here we show that peptidoglycan modification by PgdA and Adr prevent bacterial cell death, by protecting against cell lysis in the presence of lysozyme. This in turn allows S. pneumoniae to establish colonization on the mucosal surface. Although lysozyme does not lyse S. pneumoniae, interaction with lysozyme promotes the release of peptidoglycan fragments, which can be sensed by the host intracellular receptor, Nod2. Incubation of S. pneumoniae with lysozyme also led to the release of the pore-forming toxin, pneumolysin, which was required for Nod2 signaling within macrophages. Activation of Nod2 signaling led to pro-inflammatory cytokine production, and the recruitment of additional monocyte/macrophages into the upper respiratory tract. The sustained recruitment of macrophages, which required Nod2 and Toll-like receptor 2 (TLR2) signaling, aids in clearance of colonization. Nod2 sensing in response to S. pneumoniae also leads to IFNβ expression, which is heightened in a synergistic manner during influenza virus co-infection. Heightened levels of IFNβ correlated with increased pneumococcal colonization levels and decreased macrophage recruitment, which was due to direct inhibition of Nod2 signaling by IFNβ. Peptidoglycan sensing also impacted neutrophil function; the microbiota provides Nod1 ligands that are sensed by neutrophils and stimulate killing activity. Together our data suggest that host sensing of peptidoglycan is required for immune function, and also plays an important role in the host immune response to colonization by S. pneumoniae. . |
