Porphyromonas gingivalis adopts intricate and unique molecular mechanisms to survive and persist within the host: a critical update

Figures & data

Table 1. Novel Pathogenic mechanisms adopted by P. gingivalis to exaggerate periodontal inflammation.

S/No	Pathogenic mechanisms		Reference
1.	Synergistic interaction with other organisms and the development of pathobiont species	Growth of bystander or commensal microbiota The emergence of pathobiont species such as F. alocis, Peptostreptococcus stomatitis, Prevotella, Megasphaera selenomonas, and desulfobulbus Activation of intracellular nucleotide-binding oligomerization domain 1 (Nod1) A shift of nutrient requirement from protein-dependent to carbohydrate dependent Non-identity-mediated CRISPR-bacteriophage interaction Co-operative haem acquisition by the HmuY haemophore of Porphyromonas gingivalis	Kolenbrander et al., 2006 Hajishengallis et al., 2011 Jiao et al., 2014 Aruni et al., 2014 Hasegawa et al., 2006 Cady et al., 2011dr Byrne et al., 2013
2.	Survival in the host cell and neutrophil dysfunction	Regulation of expression of E-selectin on the endothelial cell surface Binding of FimA to β1 integrin receptor Induces the expression of transposases Release of serine phosphatase protein (SerB) and dephosphorylates the actin-depolymerizing molecule ‘cofilin’ Activates Heat Shock Protein (HSP) and GAPDH (glyceraldehyde 3 phosphate dehydrogenase) receptors Inhibit IL 8, cytokine-induced neutrophil chemoattractant (CINC) 2αβ Induce microRNAs (miR-105 and miR-203).	Reife et al., 2006 Darveau et al., 1995 Duran-Pinedo et al., 2014 Bainbridge et al., 2010 Huang et al., 2001 Takeuchi et al., 2013 Benakanakere et al., 2009
3.	Anti-apoptotic mechanism	Inhibition of Janus A Kinase (JAK), Phosphoinositide 3 Kinase (PI3 K), Signal Transducer of Activation (STAT), alpha-serine/threonine-protein kinase (Akt) and purinoceptor (P2X7 receptors). Activate p38, mitogen-activated protein kinase (MAPK), and extracellular-signal-regulated kinase (Erk1/2) pathways. Decrease expression of cyclin D at the G1 phase. Increase Apoptotic protease activating factor (Apaf 1), B-cell lymphoma Associated X (Bax1) and Caspase 3 production Reduce B-cell lymphoma (BCL 2) expression Regulate NLR family pyrin domain containing 3 (NLRP3) inflammasome expression	Zaric et al., 2010 Choi et al., 2013 Yilmaz et al., 2008 Song et al., 2016 Bugueno et al., 2018 Huck et al., 2015
4.	Increased proinflammatory cytokine production	Binding of LPS to Toll-like receptors (TLRs), Receptor activator of nuclear factor kappa-B ligand (RANKL) and complement receptor (CR) A shift of LPS moiety from Penta acylated to tetra acylated isoform Activation of TLR 2/4 and C5aR on the neutrophil surface LPS induced increase in Thrombospondin 1 (TSP) production and Plasminogen activator inhibitor type 1 expression Down-regulate T-helper 1 (Th 1) cells Activation of Protease-activated receptor (PAR) 2 and soluble triggering receptor (sTREM) Increase production of IL17	Lu et al., 2009 Reife et al., 2006 Gokyu et al., 2014 Na et al., 2014 Bostanci et al., 2013 Nylund et al., 2017 Moutsopoulos et al., 2012
5.	Subversion of the complement system	Inhibits all components of the complement system and degradation of its by-products (C3a and C5a) Prevents formation of membrane attack complex (MAC) by inhibiting Mannose-binding lectin (MBL), Ficolins (FCN), C3, C3b, and C4. Utilizes HRgpA gingipain to entrap the circulating C4b binding protein.	Sundqvist et al., 1985 Potempa et al., 2008 Hajishengallis et al., 2007
6.	Disruption of T cell function	Induce Th1 immune response and increase secretion of IL 1, IL6, IL10 production A decrease in levels of IL12 and increased production of Interferon-alpha Favors Th-17 activation by interaction with dendritic cells of the host	Cardoso et al., 2009 Moutsopoulos et al., 2012 Yoshimatsu et al., 2009
7.	Suppression of macrophage activity	Increase cAMP formation Reduce the expression of inducible nitric oxide synthase (iNOS) Activation of caspase 11 dependent non-canonical inflammasome in the macrophage Altered macrophage function and antigen presentation Attenuate CR3 activation in macrophages, reduce inhibition of lncRNA GAS5, with less miR-21 and more IL12 production. by inhibiting sialidase	Nathan., 2012 Moon et al., 2014 Yung et al., 2018
8.	Modulation of gene expression in the host and other bacteria	Modify levels of hemin, polyphosphate, rhein, polyphosphate, Temperature-dependent modulation of Porphyromonas gingivalis lipid A structure Upregulation of putative transposases in S. mitis and Lactobacillus casei microcolonies Upregulation of CRISPR RNA and toxin-antitoxin system proteins	Anaya-Bergman et al., 2006; Phillips et al., 2006; Al-Qutub et al., 2006 Curtis et al.,2011a Aruni et al.,2014 Jorth et al., 2012;
9.	Fratricide and altruistic ‘suicide’ of other bacteria	Release of Choline Binding protein D (CbpD), competence-induced bacteriocins (CibAB), Activation of Autolysin-Encoding Gene Activation of bacterial apoptosis endonuclease (BapE)	Duran-Pinedo et al., 2014 Eldholm et al., 2009
10.	Increased production of antioxidant species	Activation of NOX 4 receptors Increase extracellular ATP production by activation of P2X4, P2X7, JAK2, and pannexin-1 receptor Increase production of NADPH oxidase Intracellular release of endogenous antioxidants like thiol peroxidase, glutathione, superoxide dismutase, rubrerythrin	Gölz et al., 2014 Bedard et al., 2007 Wang et al., 2014 Goettsch et al., 2013 Sztukowska et al., 2002 Kikuchi et al., 2005

Figure 1. Virulence factors of P. gingivalis: P gingivalis has various virulence factors that help it to invade the host cell and evade the defense mechanisms of the host. Some of the most important adhesions of P. gingivalis include Lipopolysaccharide (LPS), Capsule, outer Membrane protein, Peptidoglycan, Major, and minor Fimbriae and Pilli. P. gingivalis also release enzymes and cytotoxic molecules such as defensins, autoinducer proteins (AI-2); 8 hydroxy 2ʹ deoxyguanosine, superoxide anions, matrix metalloproteinases, caspase-3, catalase, nucleotide-diphosphate-kinase. These enzymes help to invade the host cell, increase oxidative stress, and enhance biofilm formation. P. gingivalis is also known to release endogenous antioxidants such as thiol, peroxidase, glutathione, superoxide dismutase, rubrerythrin to protect itself from the surrounding free radicals.

Figure 2. P. gingivalis modulates the host immune response by facilitating the growth of pathobionts species and altering the function of various immune cells of the host. The weakened immune response enhances biofilm formation and oxidative stress that in turn increases the periodontal inflammation and favors the growth of P. gingivalis [Abbreviation: CR- complement receptors; TLR- Toll-like receptors; ROS-Reactive oxygen species; MMPS- matrix metalloproteinase; IL- interleukin; RANKL- Receptor activator of nuclear factor-kappa beta; TNF- Tumor Necrotic Factor-alpha; Th – T helper cells]. [Abbreviation: CR- complement receptors; TLR- Toll-like receptors; ROS-Reactive oxygen species; MMPS- matrix metalloproteinase; IL- Interleukin; RANKL- Receptor activator of nuclear factor-kappa beta; TNF- Tumor Necrotic Factor-alpha; Th – T helper cells; NOD-nucleotide-binding oligomerization domain; NF-Kb – Nuclear Factor kappa Beta].

Figure 3. Interaction of P. gingivalis with F. alocis and its effects on biofilm formation and periodontal inflammation: P. gingivalis interaction with F. alocis can modulate the innate immune response of the host as both these species auto-aggregate and express unique genes expression. P. gingivalis-F. alocis remodeling the actin and chromatin molecule, activation of autoinducer (AI) associated quorum sensing, the proliferation of the junctional epithelium, and deposition of collagen fibers in the gingival epithelial cells. The co-infection also upregulates the production of extracellular matrix adhesion proteins, CRISPRs RNA, and toxin-antitoxin system proteins that increase the adherence and colonization of P. gingivalis with other ‘Gram-positive bacteria and host tissues’, and are directly linked with increased biofilm formation. The CRISPR-RNA also helps with triggering the stress response, chaperone formation, and horizontal gene transfer among oral bacteria that favor microbial community development.

Figure 4. Modulation of immunoinflammatory response by two forms of P. gingivalis lipid A depending on the microenvironment (hemin level) and their interference in TLR4 receptor signaling downstream activation. It can regulate the inflammatory response according to changes in the environmental conditions by changing its LPS moiety [Abbreviation: LPS: lipopolysaccharide; p65: nuclear factor NF-κB protein p65 subunit; p50: nuclear factor NF-κB protein p50 subunit; 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 5. Schematic representation of the interaction between P. gingivalis and S. gordonii: P. gingivalis interacts with S. gordonii by utilizing its major (FimA) and minor fimbriae (Mfa1). FimA and Mfa1 of P. gingivalis binds to glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) and streptococcal SspA/B adhesins (SspA/B termed BAR antigen I/II) of S. gordonii, respectively The Mfa1 interactions with SspB lead to phenotypic changes with subsequent activation of tyrosine phosphorylation signal production (PTK). The increased PTK signaling causes exopolysaccharide formation that causes accretion of P. gingivalis colonies. The FimA also interacts to the α5β1-integrin receptors on gingival epithelial to facilitate bacterial entry.

Figure 6. Schematic representation Immune response pathways triggered by the activation of TLR2/TLR4/CXCR5/C5aR receptors by gingipains P. gingivalis: The gingipains of P. gingivalis degrade the C5 and C3 from the complement system and degrade them C5a and C3a. The C5a interacts with the receptors on the neutrophils, epithelial cells, and endothelium in the host to Impairs phagocytosis and increase proinflammatory cytokine. C3a also inhibits the caspase 11–dependent non-canonical inflammasome pathway and prevents the apoptosis of the cell and allows P. gingivalis to use the host cell for its growth. The C5aR-TLR2 cross-talk activated by P. gingivalis pili induced degradation of MyD88 in neutrophils. In the absence of MyD88, the co-association of C5aR-TLR2 promotes P. gingivalis infection v activation of the TIRAP-dependent PI3 K signaling pathway. This, in turn, causes an inflammatory cytokine TNF-α along with inhibition of RhoA activation and actin polymerization that impairs the process of the maturation of phagosomes and P. gingivalis phagocytosis [Abbreviation: CR- complement receptors; TLR- Toll-like receptors; 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; PI3 K: phosphoinositide-3-kinase; RhoA: Ras homolog gene family, member A; sTREM-1 – sTREM-1 – salivary Triggering Receptor Expressed on Myeloid cells 1ʹ Protease-activated receptors [PAR]-2].

Figure 7. Schematic presentation of the immunological pathways triggered by LPS of P.gingivalis.

The atypical LPS of P. gingivalis interacts with the TLR2/TLR4/CXCR5/C5aR receptors on the host cells to activate Phosphoinositide 3-kinase (PI3 K), cyclic AMP and PKA. The C5a-C5aR activation mediated by P. gingivalis gingipain-degradation of C5 synergistically enhances the production of cAMP. The combination of pili and CXCR4 helped maximize cAMP production via C5a-TLR2 cross-talk. The continuous increase in cAMP activated PKA to reduce macrophage-forming NO and destroying the bactericidal function and possible therapeutic targets. The increased cyclic AMP inhibits the release of nitric oxide that further impairs the process of transendothelial migration, chemotaxis, and phagocytosis. Arg-specific gingipains and SerB protein of P. gingivalis alters the process of actin polymerization. The altered actin affects the process of phagocytosis along with promoting the development of the pathogenic species that can indirectly increase the inflammatory process in the periodontal tissues [Abbreviation: CR- complement receptors; TLR- Toll-like receptors; 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; PI3 K: phosphoinositide-3-kinase; RhoA: Ras homolog gene family, member A]