Porphyromonas gingivalis virulence factors involved in subversion of leukocytes and microbial dysbiosis

Abstract

The oral bacterium Porphyromonas gingivalis has special nutrient requirements due to its asaccharolytic nature subsisting on small peptides cleaved from host proteins. Using proteases and other virulence factors, P. gingivalis thrives as a component of a polymicrobial community in nutritionally favorable inflammatory environments. In this regard, P. gingivalis has a number of strategies that subvert the host immune response in ways that promote its colonization and facilitate the outgrowth of the surrounding microbial community. The focus of this review is to discuss at the molecular level how P. gingivalis subverts leukocytes to create a favorable environment for a select community of bacteria that, in turn, adversely affects the periodontal tissues.

Keywords: P. gingivalis; dysbiosis; immune subversion; inflammation leukocytes; periodontitis.

Figure 1.

Manipulation of neutrophil function by P. gingivalis. (A) Model of chemokine paralysis. Under homeostatic conditions, oral bacteria are kept at bay by steady recruitment of neutrophils following a gradient of IL-8 production by the gingival epithelium. P. gingivalis can manipulate the IL-8 gradient by secreting SerB, an enzyme that dephosphorylates the p65 subunit of NF-κB thereby inhibiting translocation into the nucleus and preventing IL-8 transcription. The result is chemokine paralysis that disrupts the recruitment of neutrophils into the junctional epithelium and control of the outgrowth of oral bacteria. (B) Model of Neutrophil subversion by P. gingivalis that leads to dysbiotic inflammation. Due to C5a ligand generation by Arg-specific gingipains coupled with potent TLR2 agonists (e.g., lipoproteins), P. gingivalis is able to co-activate C5aR and TLR2 resulting in Smurf1-dependent MyD88 degradation thus preventing an antimicrobial response. This signaling event also induces Mal- and PI3K-dependent inhibition of RhoA, thereby preventing phagocytosis while the same subversive pathway mediates inflammatory responses. In total, P. gingivalis can successfully decouple antimicrobial killing from a nutritionally favorable inflammatory response in neutrophils. This mechanism provides bystander support to neighboring bacteria.

Figure 2.

P. gingivalis exploitation of macrophages and dendritic cells. (A) P. gingivalis hijacking of the macrophage. P. gingivalis associates with lipid rafts on macrophages and causes the co-aggregation of CXCR4 and TLR2 with its FimA fimbriae and associated proteins. The result is an inside-out signaling event that causes complement receptor 3 (CR3) to undergo a conformational change to a ‘high affinity’ structure. P. gingivalis then utilizes CR3 for macrophage internalization. In addition to the inside-out singaling, TLR2 and CXCR4 cause activation of cAMP and subsequent PKA-dependent inhibition of inducible nitrogen oxide synthase (iNOS) ultimately preventing the bacterial killing ability of the macrophage. An additional mechanism by which P. gingivalis can increase its survival within the macrophage involves its capacity to inhibit non-canonical inflammasome activation and hence pyroptosis, a proinflammatory mechanism of lytic cell death that protects the host against infection. Since the caspase 11-dependent noncanonical mechanism of inflammasome activation is triggered by intracellular LPS, it is likely that P. gingivalis, or at least its LPS, escapes to the cytosol. (B) P. gingivalis manipulation of dendritic cell entry. P. gingivalis has a unique fimbrial protein, Mfa1, that specifically interacts with DC-SIGN on the dendritic cell surface. This binding phenomenon allows P. gingivalis to gain entry into the dendritic cell where it can survive and may be visualized within a vacuole. P. gingivalis-manipulated dendritic cells can also harbor other bacterial species as well. It is currently unclear whether P. gingivalis has to escape the vacuole in order to survive as is the case with other cell types.