title: Genetic modulation of TLR8 response following bacterial phagocytosis.
abstract: Human Toll-like receptors (TLRs) TLR7, TLR8, and TLR9 are important immune sensors of foreign nucleic acids encountered by phagocytes. Although there is growing evidence implicating TLR7 and TLR9 in the detection of intracellular pathogenic bacteria, characterization of such a role for TLR8 is currently lacking. A recent genetic study has correlated the presence of a TLR8 single nucleotide polymorphism (SNP) (rs3764880:A>G; p.Met1Val) with the development of active tuberculosis, suggesting a role for TLR8 in the detection of phagosomal bacteria. Here we provide the first direct evidence that TLR8 sensing is activated in human monocytic cells following Helicobacter pylori phagocytosis. In addition, we show that rs3764880 fine tunes translation of the two TLR8 main isoforms, without affecting protein function. Although we show that TLR8 variant 2 (TLR8v2) is the prevalent form of TLR8 contributing to TLR8 function, we also uncover a role for the TLR8 long isoform (TLR8v1) in the positive regulation of TLR8 function in CD16(+)CD14(+) differentiated monocytes. Thus, TLR8 sensing can be activated following bacterial phagocytosis, and rs3764880 may play a role in the modulation of TLR8-dependent microbicidal response of infected macrophages.
authors.affiliation: Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Gantier
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Irving
authors.forename: Maria
authors.initials: M
authors.lastname: Kaparakis-Liaskos
authors.forename: Dakang
authors.initials: D
authors.lastname: Xu
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Evans
authors.forename: Paul U
authors.initials: PU
authors.lastname: Cameron
authors.forename: James A
authors.initials: JA
authors.lastname: Bourne
authors.forename: Richard L
authors.initials: RL
authors.lastname: Ferrero
authors.forename: Matthias
authors.initials: M
authors.lastname: John
authors.forename: Mark A
authors.initials: MA
authors.lastname: Behlke
authors.forename: Bryan R G
authors.initials: BR
authors.lastname: Williams
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D002465:Cell Movement; D025461:Feedback, Physiological; D016480:Helicobacter pylori / Q000502:physiology*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism / Q000382:microbiology*; D010587:Phagocytosis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D017452:Receptors, IgG / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D018950:Lipopolysaccharide Receptors; D020033:Protein Isoforms; D017452:Receptors, IgG; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8