Porphyromonas Gingivalis Virulence Factors and their Role in Undermining Antimicrobial Defenses and Host Cell Death Programs in the Pathobiology of Chronic Periodontal Disease

Płonczyńska, Alicja; Prucsi, Zsombor; Sochalska, Maja; Potempa, Jan

doi:10.2478/am-2025-0001

Figures & Tables

Porphyromonas gingivalis virulence factors and LPS structure.Pg expresses various virulence factors: long fimbriae (FimA type), short fimbriae (Mfa1), lipopolysaccharide (LPS), outer membrane vesicles (OMVs), which can contain gingipains. Pg-LPS exists in two forms: tetra-acylated, and penta-acylated with a different pro-inflammatory potency (Al-Qutub et al., 2006; Darveau, 2010) Created in BioRender. https://BioRender.com/s67b276

Fig. 2.

Macrophage polarization pathways.Upon various stimulus through cell surface receptors macrophage can activate M1 or M2 polarization genes. M1 polarization is related with TLRs, and cytokines receptors, such as TNF-R or IFNγ receptor. NF-κB signaling pathway is the main regulator of M1 polarization genes, but the pro-inflammatory phenotype can be also activated through IRF3, MAP kinase or STAT (members 1, 2, 4, 5). Alternatively, in response to anti-inflammatory cytokines recognized by cytokine receptors, PI3K/Akt and STAT (members 3, 6) pathways can be triggered, leading to activation of M2 polarization genes and inhibiting M1 profile (Kerneur et al., 2022; Xia et al., 2023). AP1, activator protein 1; ARG1, arginase 1; BTK, Bruton’s tyrosine kinase; CSFR, colony-stimulating factors receptor; FIZZ1, found in inflammatory zone 1; GM-CSFR, granulocyte-macrophage colony-stimulating factor receptor; IFNγ, interferon gamma; IL-4R, interleukin-4 receptor; IL-10R, interleukin-10 receptor; IRAK1/4, interleukin-1 receptor-associated kinases 1/4; IRF3/9, interferon regulatory factor 3/9; JAK, Janus activated kinases; MAPK, mitogen-activated protein kinase; MHCII, major histocompatibility complex class II; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOS2, nitric oxide synthase 2; PI3K/Akt, phosphatidylinositol 3-kinase/Akt kinase; STAT, signal transducer and activator of transcription; TGFβ, transforming growth factor β; TLR, toll-like receptor; TNFα, tumor necrosis factor alpha; TNF-R, TNF receptor; TRAF6, TNF receptor associated factor 6; TRIF, TIR-domain-containing adapter-inducing interferon-β; Ym1, chitinase-like protein 3 (Chil3); Created in BioRender. https://BioRender.com/v80l298

Apoptosis pathways and P. gingivalis.Upon pro-apoptotic signals, dominating BH3-only proteins inhibit anti-apoptotic members of Bcl-2 family (Bcl-2, Mcl-1, Bcl-xL, Bcl-w, Bfl-1), enabling BAX and BAK oligomerization, and mitochondrion permeabilization. After formation of apoptosome with APAF1, cytochrome c, and pro-capsase-9, the caspase cascade is activated, leading to apoptosis. Alternatively, the activation of death receptors leads to caspase-8 activation, and subsequently intrinsic pathway activation or directly activating caspase cascade (Kayagaki et al., 2024). In sentinel cells, Pg can alter the expression of Bfl-1, Bcl-2, APAF1, XIAP, and caspases 3/7 and 9. APAF1, apoptotic peptidase activating factor 1; FADD, Fas-associated death domain; RIPK1, receptor-interacting serine/threonine-protein kinase 1; SMAC, second mitochondria-derived activator of caspases; TRADD, TNFR1 associated death domain protein; XIAP, X-linked inhibitor of apoptosis; Created in BioRender. https://BioRender.com/t45c156

Fig. 4.

Pyroptosis pathways and P. gingivalis.Upon TLRs stimulation, NF-κB upregulates the expression of ASC, NLRP3, and pro-caspase-1, which subsequently form inflammasome. Caspase-1 activates IL-1β, IL-18, and cleaves GSDMD into pore forming domains, which oligomerize in cell membrane, creating pores. Alternatively, caspase-8 can activate inflammasome, and IL-1β. Intracellular presence of PAMPs, especially LPS, is recognized by caspase-4/5/11, which upon oligomerization can cleave GSDMD and trigger pore formation, and activate IL-18. Pro-apoptotic caspase-3 acts as a GSDMD inhibitor (Kayagaki et al., 2024). Pg can modulate pyroptosis through changes in the activation of NF-κB, caspase-1, 4, and 3, the expression profile of ASC, NLRP3, pro-capsase-1, inflammasome, GSDMD, and secretion of IL-1β and IL-18. ASC, apoptotic speck protein containing a caspase recruitment domain; BTK, Bruton’s tyrosine kinase; FADD, Fas-associated death domain; GSDMD, gasdermin D; GSDMD-N, cleaved N-terminal GSDMD; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, nucleotide-binding domain, leucine-rich repeat-containing family, and pyrin domain-containing-3/caspase recruitment domain; PAPMs, pathogen associated molecular patterns; RIPK1, receptor-interacting serine/threonine-protein kinase 1; TLR, toll-like receptor; TRADD, TNFR1 associated death domain protein; Created in BioRender. https://BioRender.com/l81p084

Necroptosis pathways and P. gingivalis.The activation of death receptors triggers formation of complex I, which activates NF-κB pathway and pro-survival genes. Upon inhibition of RIPK1 ubiquitination by CYLD, complex IIa is formed. The cleavage of RIPK1 by caspase-8 activates apoptosis pathway. If pro-caspase-8 remains inactive by cFLIP, complex IIb is formed. Subsequently, phosphorylation of RIPK1, and RIPK3, and their oligomerization, together with phosphorylated MLKL leads to necrosome formation. Necrosome translocates to cellular membranes, forming pores, which leads to necroptosis (Dhuriya & Sharma, 2018; Holler et al., 2000; O’Donnell et al., 2011). Pg modulates necroptosis pathways targeting RIPK3, and MLKL. cIAP1/2, cellular inhibitor of apoptosis protein 1/2; CYLD, cylindromatosis; FADD, Fas-associated death domain; MLKL, mixed lineage kinase domain-like; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; RIPK1/3, receptor-interacting serine/threonine-protein kinases 1/3; SMAC, second mitochondria-derived activator of caspases; TRADD, TNFR1 associated death domain protein; TRAF, TNF receptor-associated factor; TRIF, TIR-domain-containing adapter-inducing interferon-β; Created in BioRender. https://BioRender.com/r22c556

Porphyromonas Gingivalis Virulence Factors and their Role in Undermining Antimicrobial Defenses and Host Cell Death Programs in the Pathobiology of Chronic Periodontal Disease

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