Immunological Pathways Triggered by Porphyromonas gingivalis and Fusobacterium nucleatum: Therapeutic Possibilities?

Abstract

Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum (F. nucleatum) are Gram-negative anaerobic bacteria possessing several virulence factors that make them potential pathogens associated with periodontal disease. Periodontal diseases are chronic inflammatory diseases of the oral cavity, including gingivitis and periodontitis. Periodontitis can lead to tooth loss and is considered one of the most prevalent diseases worldwide. P. gingivalis and F. nucleatum possess virulence factors that allow them to survive in hostile environments by selectively modulating the host's immune-inflammatory response, thereby creating major challenges to host cell survival. Studies have demonstrated that bacterial infection and the host immune responses are involved in the induction of periodontitis. The NLRP3 inflammasome and its effector molecules (IL-1β and caspase-1) play roles in the development of periodontitis. We and others have reported that the purinergic P2X7 receptor plays a role in the modulation of periodontal disease and intracellular pathogen control. Caspase-4/5 (in humans) and caspase-11 (in mice) are important effectors for combating bacterial pathogens via mediation of cell death and IL-1β release. The exact molecular events of the host's response to these bacteria are not fully understood. Here, we review innate and adaptive immune responses induced by P. gingivalis and F. nucleatum infections and discuss the possibility of manipulations of the immune response as therapeutic strategies. Given the global burden of periodontitis, it is important to develop therapeutic targets for the prophylaxis of periodontopathogen infections.

Figure 1

Two forms of P. gingivalis lipid A depending on the microenvironment and their interference in TLR4 receptor signaling downstream activation. Legend: LPS: lipopolysaccharide; p65: nuclear factor NF-κB protein p65 subunit; p50: nuclear factor NF-κB protein p50 subunit; Rel A: v-rel reticuloendotheliosis viral oncogene homolog A; TLR4: Toll-like receptor-4; TRAF 6: tumor necrosis factor receptor-associated factor 6; TRIF: TIR-domain-containing adapter-inducing interferon-β; TRAM: TRIF-related adaptor molecule.

Figure 2

Structural chemical differences in lipid A of F. nucleatum and P. gingivalis and their interaction with TLR4. Legend: MyD88: myeloid differentiation primary response 88. TLR4: Toll-like receptor-4; -: antagonize TLR4 activation; +++: strong TLR4 agonistic response.

Figure 3

Immune response pathways triggered by the activation of TLR2/TLR4 by F. nucleatum and P. gingivalis bacteria and possible therapeutic targets. Legend: CXCR4: C-X-C chemokine receptor type 4; cAMP: cyclic adenosine monophosphate; iNOS: inducible nitric oxide synthase; Mal: MyD88 adapter-like; p38MAPK: mitogen-activated protein kinase p38; PKA: protein kinase A; PI3K: phosphoinositide-3-kinase; RhoA: Ras homolog gene family, member A.

Figure 4

Activation of purinergic P2X7 receptor and inflammasome by the bacterium F. nucleatum or P. gingivalis and possible therapeutic targets.

Figure 5

Expression and levels of cytokines, receptors, and inflammasome in immunological and nonimmune cells and in animal models induced by P. gingivalis or F. nucleatum. Adapted from [195].