title: Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis.
abstract: Certain low-abundance bacterial species, such as the periodontitis-associated oral bacterium Porphyromonas gingivalis, can subvert host immunity to remodel a normally symbiotic microbiota into a dysbiotic, disease-provoking state. However, such pathogens also exploit inflammation to thrive in dysbiotic conditions. How these bacteria evade immunity while maintaining inflammation is unclear. As previously reported, P. gingivalis remodels the oral microbiota into a dysbiotic state by exploiting complement. Now we show that in neutrophils P. gingivalis disarms a host-protective TLR2-MyD88 pathway via proteasomal degradation of MyD88, whereas it activates an alternate TLR2-Mal-PI3K pathway. This alternate TLR2-Mal-PI3K pathway blocks phagocytosis, provides "bystander" protection to otherwise susceptible bacteria, and promotes dysbiotic inflammation in vivo. This mechanism to disengage bacterial clearance from inflammation required an intimate crosstalk between TLR2 and the complement receptor C5aR and can contribute to the persistence of microbial communities that drive dysbiotic diseases.
authors.affiliation: University of Pennsylvania, School of Dental Medicine, Department of Microbiology, Philadelphia, PA 19104, USA.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Maekawa
authors.affiliation: University of Louisville, Center for Oral Health and Systemic Disease, Louisville, KY 40292, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Krauss
authors.affiliation: University of Pennsylvania, School of Dental Medicine, Department of Microbiology, Philadelphia, PA 19104, USA.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Abe
authors.affiliation: University of Louisville, Center for Oral Health and Systemic Disease, Louisville, KY 40292, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Jotwani
authors.affiliation: Cardiff University School of Medicine, Institute of Infection and Immunity, Cardiff CF14 4XN, UK.
authors.forename: Martha
authors.initials: M
authors.lastname: Triantafilou
authors.affiliation: Cardiff University School of Medicine, Institute of Infection and Immunity, Cardiff CF14 4XN, UK.
authors.forename: Kathy
authors.initials: K
authors.lastname: Triantafilou
authors.affiliation: Queen Mary University of London, Centre for Immunology and Infectious Disease, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Hashim
authors.affiliation: Hebrew University, Hadassah Dental School, Jerusalem 12272, Israel.
authors.forename: Shifra
authors.initials: S
authors.lastname: Hoch
authors.affiliation: Queen Mary University of London, Centre for Immunology and Infectious Disease, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Curtis
authors.affiliation: Hebrew University, Hadassah Dental School, Jerusalem 12272, Israel.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nussbaum
authors.affiliation: University of Pennsylvania, Perelman School of Medicine, Department of Pathology and Laboratory Medicine, Philadelphia, PA 19104, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.affiliation: University of Pennsylvania, School of Dental Medicine, Department of Microbiology, Philadelphia, PA 19104, USA. Electronic address: geoh@upenn.edu.
authors.forename: George
authors.initials: G
authors.lastname: Hajishengallis
mesh_terms: D000818:Animals; D016866:Bacteroidaceae Infections / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology; D064806:Dysbiosis / Q000276:immunology / Q000382:microbiology*; D054884:Host-Pathogen Interactions / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology; D010518:Periodontitis / Q000276:immunology / Q000382:microbiology*; D010587:Phagocytosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016966:Porphyromonas gingivalis / Q000276:immunology / Q000472:pathogenicity*; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: C488033:C5AR1 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D044087:Receptor, Anaphylatoxin C5a; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D003165:Complement System Proteins; D019869:Phosphatidylinositol 3-Kinases