TY - JOUR
T1 - Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis
AU - Maekawa, Tomoki
AU - Krauss, Jennifer L.
AU - Abe, Toshiharu
AU - Jotwani, Ravi
AU - Triantafilou, Martha
AU - Triantafilou, Kathy
AU - Hashim, Ahmed
AU - Hoch, Shifra
AU - Curtis, Michael A.
AU - Nussbaum, Gabriel
AU - Lambris, John D.
AU - Hajishengallis, George
N1 - 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.
PY - 2014/6/11
Y1 - 2014/6/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84902458366&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2014.05.012
DO - 10.1016/j.chom.2014.05.012
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C2 - 24922578
AN - SCOPUS:84902458366
SN - 1931-3128
VL - 15
SP - 768
EP - 778
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 6
ER -