Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis

Tomoki Maekawa, Jennifer L. Krauss, Toshiharu Abe, Ravi Jotwani, Martha Triantafilou, Kathy Triantafilou, Ahmed Hashim, Shifra Hoch, Michael A. Curtis, Gabriel Nussbaum, John D. Lambris, George Hajishengallis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

304 Scopus citations

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.

Original languageAmerican English
Pages (from-to)768-778
Number of pages11
JournalCell Host and Microbe
Volume15
Issue number6
DOIs
StatePublished - 11 Jun 2014

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health (AI068730 to J.D.L.; DE015254 and DE021685 to G.H.), the European Commission (FP7-DIREKT 602699 to J.D.L.), and the MRC (UK) (G0900408 to M.A.C.). The authors declare no financial conflicts of interest.

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