title: Toll-Like Receptor 3/TRIF-Dependent IL-12p70 Secretion Mediated by Streptococcus pneumoniae RNA and Its Priming by Influenza A Virus Coinfection in Human Dendritic Cells.
abstract: A functional immune response is crucial to prevent and limit infections with Streptococcus pneumoniae. Dendritic cells (DCs) play a central role in orchestrating the adaptive and innate immune responses by communicating with other cell types via antigen presentation and secretion of cytokines. In this study, we set out to understand how pneumococci activate human monocyte-derived DCs to produce interleukin-12 (IL-12) p70, an important cytokine during pneumococcal infections. We show that IL-12p70 production requires uptake of bacteria as well as the presence of the adaptor molecule TRIF, which is known to transfer signals of Toll-like receptor 3 (TLR3) or TLR4 from the endosome into the cell. While TLR4 is redundant for IL-12p70 production in DCs, we found that TLR3 is required to induce full IL-12p70 secretion. Influenza A virus (IAV) infection of DCs did not induce IL-12p70 but markedly upregulated TLR3 expression that during coinfection with S. pneumoniae significantly enhanced IL-12p70 secretion. Finally, we show that pneumococcal RNA can act as a bacterial stimulus for TLR3 and that it is a key signal to induce IL-12p70 production during challenge of DCs with pneumococci.
  
  
  OBJECTIVE
  Streptococcus pneumoniae, a common colonizer of the nose, is the causative agent of severe and deadly diseases. A well-orchestrated immune response is vital to prevent and limit these diseases. Dendritic cells (DCs) reside in the mucosal linings of the lungs and sample antigens. They are activated by pathogens to present antigens and secrete cytokines. While many studies focus on murine models, we focused our work on human monocyte-derived DCs. We found that pneumococcal RNA is an important stimulus in DCs to activate the endosomal receptor TLR3, a receptor previously not identified to sense pneumococci, and its adaptor molecule TRIF. This leads to secretion of the cytokine interleukin-12 (IL-12). Severe pneumococcal pneumonia occurs closely after influenza A virus (IAV) infection. We show that IAV infection upregulates TLR3 in DCs, which sensitizes the cells to endosomal pneumococcal RNA. This new insight contributes to unlock the interplay between pneumococci, IAV, and humans.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Laura
authors.initials: L
authors.lastname: Spelmink
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vicky
authors.initials: V
authors.lastname: Sender
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karina
authors.initials: K
authors.lastname: Hentrich
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuri
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Laura
authors.initials: L
authors.lastname: Plant
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden birgitta.henriques@ki.se.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Henriques-Normark
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D060085:Coinfection / Q000276:immunology / Q000382:microbiology / Q000821:virology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D006801:Humans; D009980:Influenza A virus / Q000276:immunology* / Q000502:physiology; D007251:Influenza, Human / Q000235:genetics / Q000276:immunology* / Q000821:virology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D009000:Monocytes / Q000276:immunology; D011008:Pneumococcal Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D012329:RNA, Bacterial / Q000235:genetics / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D012329:RNA, Bacterial; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D018664:Interleukin-12