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

Abstract

SUMMARY 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.

Mucosal Microbiome in Patients with Recurrent Aphthous Stomatitis

“…Yet, recent studies have shown the ability of P. gingivalis to inhibit phagocytosis of otherwise susceptible bacteria and hence promote dysbiosis itself (Maekawa et al 2014). The coinciding decrease of Streptococcaceae species was equally observed in active ulcers only.…”

“…As suggested for periodontal disease (Kumar et al 2005), targets of early stages of inflammation in RAS may be pathobionts that are overrepresented during global perturbation of the normal oral microbiota. The role of Porphyromonas gingivalis in periodontal disease has recently been emphasized by demonstration of its ability to promote dysbiosis of oral microbiota (Maekawa et al 2014).…”

<i>Porphyromonas Gingivalis</i> Elevated High-Mobility Group Box 1 Levels After Myocardial Infarction in Mice

“…27,28) Male C57BL/6J wild type mice (7 weeks, 20-25 g) were obtained from Japan Clea, Co. (Tokyo, Japan). All animal care and experimental procedures were approval by the Tokyo Medical and Dental University Guide for the Care and Use of Laboratory Animals (permit number: 0150166 A) and by the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.…”

Non-conventional therapeutics for oral infections

“…Despite this, it is known that the RgP gingipains act in concert with Kgp gingipain to contribute to the entire virulence of the organism, particularly through disruption of the host complement system. 81 Therefore, a single agent that inhibits both gingipain proteases has clinical therapeutic potential. Kataoka et al 82 recently developed such a dual inhibitor through structure-based drug design.…”