Streptococcus pneumoniaeStimulates a STING- and IFN Regulatory Factor 3-Dependent Type I IFN Production in Macrophages, which Regulates RANTES Production in Macrophages, Cocultured Alveolar Epithelial Cells, and Mouse Lungs

Abstract

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. In this study, we examine an innate immune recognition pathway that senses pneumococcal infection, triggers type I IFN production, and regulates RANTES production. We found that human and murine alveolar macrophages as well as murine bone marrow macrophages, but not alveolar epithelial cells, produced type I IFNs upon infection with S. pneumoniae. This response was dependent on the pore-forming toxin pneumolysin and appeared to be mediated by a cytosolic DNA-sensing pathway involving the adapter molecule STING and the transcription factor IFN regulatory factor 3. Indeed, DNA was present in the cytosol during pneumococcal infection as indicated by the activation of the AIM2 inflammasome, which is known to sense microbial DNA. Type I IFNs produced by S. pneumoniae-infected macrophages positively regulated gene expression and RANTES production in macrophages and cocultured alveolar epithelial cells in vitro. Moreover, type I IFNs controlled RANTES production during pneumococcal pneumonia in vivo. In conclusion, we identified an immune sensing pathway detecting S. pneumoniae that triggers a type I IFN response and positively regulates RANTES production.

Pneumolysin-Dependent Calpain Activation and Interleukin-1α Secretion in Macrophages Infected with Streptococcus pneumoniae

“…Moreover, in this study, phagocytosis of bacteria by host macrophages was involved in S. pneumoniae-induced IL-1␣ production. We and others previously suggested that S. pneumoniae cells internalized by macrophages underwent rapid death and released PLY, thereby destabilizing phagosomal membranes in a PLY-dependent manner (11,35). Interestingly, phagosomal destabilization by particulate NLRP3 activators has been proposed to facilitate the production of IL-1␣ independently of the inflammasome machinery (30).…”

Studies on cell junctions in an ex vivo human lung infection model

“…Ex vivo human lung tissue and cells were infected with S. pneumoniae D39 wild type [243,244] or S. pneumoniae D39Δply [245], carrying a pneumolysin deletion mutation [246], or S. pneumoniae D39ΔspxB with a deletion of the pyruvate oxidase gen [247]. For in vitro experiments, cells were infected with pneumococci deficient of the capsule (D39Δcps) [248] or double deficient mutants of the capsule and pneumolysin (D39ΔcpsΔply) [245].…”

“…For in vitro experiments, cells were infected with pneumococci deficient of the capsule (D39Δcps) [248] or double deficient mutants of the capsule and pneumolysin (D39ΔcpsΔply) [245].…”

The C-type lectin receptor Mincle binds to Streptococcus pneumoniae but plays a limited role in the anti-pneumococcal innate immune response

“…Among NOD-like receptors (NLRs), NOD2 recognizes pneumococcal peptidoglycan and NLRP3 is activated by PLY [12][13][14][15]. Moreover, AIM2 as well as another STING-dependent cytosolic DNA sensor detect pneumococcal nucleic acid in the host cell cytosol [7,12]. These receptors primarily regulate the production of NF-κB-dependent proinflammatory mediators, IL-1 family cytokines, and type I IFNs.…”

“…Important virulence factors of S. pneumoniae are the exotoxin pneumolysin (PLY) [3], and the polysaccharide capsule that inhibits phagocytosis, complement factor binding, and entrapment by neutrophil extracellular traps [4][5][6]. The innate immune system detects S. pneumoniae through pattern recognition receptors (PRRs) that belong to different protein families and functional classes [7,8]. For example, the Toll-like receptor (TLR) members TLR2 and TLR9 detect pneumococcal cell wall components and CpG-rich DNA, respectively [9][10][11].…”