title: Primary immunodeficiency to pneumococcal infection due to a defect in Toll-like receptor signaling.
abstract: OBJECTIVE
  The role of human Toll-like receptors (TLRs) in initiating protective immune responses in vivo is not well understood. We investigated the role of TLR signaling in defense against infection in a 3-year-old boy with a severe defect resulting in recurrent Streptococcus pneumoniae bacteremia.
  
  
  METHODS
  After classic immunodeficiencies were ruled out, the patient's mononuclear cells, macrophages, and dendritic cells (DCs) were studied. TLR signaling responses to a range of TLR- and interleukin-1 receptor (IL-1R)-specific agonists were investigated pre- and posttranscriptionally by measuring NF-kappaB translocation and cytokine mRNA and protein expression.
  
  
  RESULTS
  The patient's monocytic cells were profoundly deficient in cytokine production in response to a range of microbial-derived TLR agonists and to recombinant IL-1beta or IL-18. Lipopolysaccharide (LPS)-induced translocation of NF-kappaB p50 and p65 and the kinetics of LPS-induced cytokine mRNA transcription were normal except for IL-6 and IL-12p40, which were poorly transcribed. Despite deficient responses to TLR agonists by the patient's DCs and B cells, CD40L responses were normal.
  
  
  CONCLUSIONS
  We describe a patient with deficient TLR-mediated cytokine production with intact interleukin receptor-associated kinase (IRAK)-4 expression, NF-kappaB translocation, and enhanced susceptibility to infection. This patient demonstrates that TLR signaling, in the presence of intact antibody responses, may be a nonredundant requirement for defense against pyogenic infections.
authors.affiliation: Division of Infectious and Immunological Diseases, British Columbia's Research Institute for Child and Family Health, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Currie
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Davidson
authors.forename: Gregor S D
authors.initials: GS
authors.lastname: Reid
authors.forename: Simi
authors.initials: S
authors.lastname: Bharya
authors.forename: Kelly L
authors.initials: KL
authors.lastname: MacDonald
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Devon
authors.forename: David P
authors.initials: DP
authors.lastname: Speert
mesh_terms: D016470:Bacteremia / Q000382:microbiology; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007223:Infant; D053592:Interleukin-1 Receptor-Associated Kinases; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D009000:Monocytes / Q000276:immunology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011008:Pneumococcal Infections / Q000276:immunology*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology*; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013296:Streptococcus pneumoniae; D051193:Toll-Like Receptors
chemical_list: D016207:Cytokines; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D017853:Phosphotransferases (Alcohol Group Acceptor); D053592:Interleukin-1 Receptor-Associated Kinases