title: Reduced PICD in Monocytes Mounts Altered Neonate Immune Response to Candida albicans.
abstract: BACKGROUND
  Invasive fungal infections with Candida albicans (C. albicans) occur frequently in extremely low birthweight (ELBW) infants and are associated with poor outcome. Phagocytosis of C.albicans initializes apoptosis in monocytes (phagocytosis induced cell death, PICD). PICD is reduced in neonatal cord blood monocytes (CBMO).
  
  
  OBJECTIVE
  Phagocytosis of C. albicans causes PICD which differs between neonatal monocytes (CBMO) and adult peripheral blood monocytes (PBMO) due to lower stimulation of TLR-mediated immune responses.
  
  
  METHODS
  The ability to phagocytose C. albicans, expression of TLRs, the induction of apoptosis (assessment of sub-G1 and nick-strand breaks) were analyzed by FACS. TLR signalling was induced by agonists such as lipopolysaccharide (LPS), Pam3Cys, FSL-1 and Zymosan and blocked (neutralizing TLR2 antibodies and MYD88 inhibitor).
  
  
  RESULTS
  Phagocytic indices of PBMO and CBMO were similar. Following stimulation with agonists and C. albicans induced up-regulation of TLR2 and consecutive phosphorylation of MAP kinase P38 and expression of TNF-α, which were stronger on PBMO compared to CBMO (p < 0.005). Downstream, TLR2 signalling initiated caspase-3-dependent PICD which was found reduced in CBMO (p < 0.05 vs PBMO).
  
  
  CONCLUSIONS
  Our data suggest direct involvement of TLR2-signalling in C. albicans-induced PICD in monocytes and an alteration of this pathway in CBMO.
authors.affiliation: Department of Neonatology, University Children's Hospital, Aachen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Dreschers
authors.affiliation: Department of Neonatology, University Children's Hospital, Aachen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Saupp
authors.affiliation: Institute of Medical Microbiology, University Children's Hospital, Aachen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Hornef
authors.affiliation: Department of Environmental Medicine, University Children's Hospital, Aachen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Prehn
authors.affiliation: Department of Neonatology, University Children's Hospital, Aachen, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Platen
authors.affiliation: Department of Microbiology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Morschhäuser
authors.affiliation: Department of Neonatology, University Children's Hospital, Aachen, Germany.
authors.forename: Thorsten W
authors.initials: TW
authors.lastname: Orlikowsky
mesh_terms: D000328:Adult; D017209:Apoptosis; D002176:Candida albicans / Q000472:pathogenicity*; D058365:Candidiasis, Invasive / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology; D006801:Humans; D007231:Infant, Newborn; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010587:Phagocytosis; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D015054:Zymosan / Q000494:pharmacology
chemical_list: D016207:Cytokines; D004075:Diglycerides; C460864:FSL-1 lipoprotein, synthetic; D008070:Lipopolysaccharides; D008074:Lipoproteins; D009842:Oligopeptides; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; C061108:N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine; D015054:Zymosan