Porphyromonas gingivalis Manipulates Complement and TLR Signaling to Uncouple Bacterial Clearance from Inflammation and Promote Dysbiosis

• Published in: Cell host & microbe Vol. 15; no. 6; pp. 768 - 778
• Main Authors: Maekawa, Tomoki, Krauss, Jennifer L., Abe, Toshiharu, Jotwani, Ravi, Triantafilou, Martha, Triantafilou, Kathy, Hashim, Ahmed, Hoch, Shifra, Curtis, Michael A., Nussbaum, Gabriel, Lambris, John D., Hajishengallis, George
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.06.2014
• Subjects: Animals; Bacteroidaceae Infections - immunology; Complement System Proteins - immunology; Dysbiosis - immunology; Dysbiosis - microbiology; Host-Pathogen Interactions - immunology; Mice; Mice, Mutant Strains; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Neutrophils - immunology; Neutrophils - microbiology; Periodontitis - immunology; Periodontitis - microbiology; Phagocytosis; Phosphatidylinositol 3-Kinases - metabolism; Porphyromonas gingivalis - immunology; Porphyromonas gingivalis - pathogenicity; Receptor, Anaphylatoxin C5a - genetics; Receptor, Anaphylatoxin C5a - immunology; Receptor, Anaphylatoxin C5a - metabolism; Signal Transduction; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - immunology; Toll-Like Receptor 2 - metabolism
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2014.05.012

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. [Display omitted] •P. gingivalis degrades MyD88 and interferes with the neutrophil killing function•P. gingivalis activates PI3K, which blocks phagocytosis and promotes inflammation•These mechanisms require crosstalk between complement receptor C5aR and TLR2•This crosstalk protects P. gingivalis and bystander bacteria and promotes dysbiosis Bacteria that exploit inflammation to thrive in dysbiotic diseases need to evade killing without blocking the overall host response. Maekawa et al. uncover how Porphyromonas gingivalis subverts complement and Toll-like receptor signaling to block phagocytic killing while promoting inflammation. These effects provide “bystander” protection to the entire community and perpetuate dysbiosis.