title: Streptococcus pneumoniae evades human dendritic cell surveillance by pneumolysin expression.
abstract: Dendritic cells (DCs) protect the respiratory epithelium via induction of innate immune responses and priming of naïve T cells during the initiation of adaptive immunity. Streptococcus pneumoniae, a commonly carried asymptomatic member of the human nasopharyngeal microflora, can cause invasive and inflammatory diseases and the cholesterol-dependent cytotoxin pneumolysin is a major pneumococcal virulence factor implicated in compounding tissue damage and mediating inflammatory responses. While most studies examining the impact of pneumolysin have been based on murine models, we have focused this study on human DC responses. We show that expression of haemolytic pneumolysin inhibits human DC maturation, induction of proinflammatory cytokines and activation of the inflammasome. Furthermore, intracellular production of pneumolysin induces caspase-dependent apoptosis in infected DCs. Similarly, clinical isolates with non-haemolytic pneumolysin were more proinflammatory and caused less apoptosis compared to clonally related strains with active pneumolysin. This study describes a novel role of pneumolysin in the evasion of human DC surveillance that could have a profound clinical impact upon inflammatory disease progression and highlights the need to study human responses to human-specific pathogens.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels väg 16, Stockholm SE-171 77, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Littmann
authors.forename: Barbara
authors.initials: B
authors.lastname: Albiger
authors.forename: Anne
authors.initials: A
authors.lastname: Frentzen
authors.forename: Staffan
authors.initials: S
authors.lastname: Normark
authors.forename: Birgitta
authors.initials: B
authors.lastname: Henriques-Normark
authors.forename: Laura
authors.initials: L
authors.lastname: Plant
mesh_terms: D000818:Animals; D017209:Apoptosis; D016667:Bacterial Capsules / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000382:microbiology*; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D051379:Mice; D009154:Mutation; D011008:Pneumococcal Infections / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D012703:Serotyping; D013296:Streptococcus pneumoniae / Q000145:classification / Q000235:genetics / Q000472:pathogenicity*; D013301:Streptolysins / Q000235:genetics* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D016207:Cytokines; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; D020169:Caspases