Subversion of Innate Immunity by Periodontopathic Bacteria via Exploitation of Complement Receptor-3

Department of Periodontics/Oral Health and Systemic Disease, University of Louisville School of Dentistry, Louisville, KY 40292, USA.
Advances in Experimental Medicine and Biology (Impact Factor: 1.96). 02/2008; 632:203-19. DOI: 10.1007/978-0-387-78952-1_15
Source: PubMed


The capacity of certain pathogens to exploit innate immune receptors enables them to undermine immune clearance and persist in their host, often causing disease. Here we review subversive interactions of Porphyromonas gingivalis, a major periodontal pathogen, with the complement receptor-3 (CR3; CD11b/CD18) in monocytes/macrophages. Through its cell surface fimbriae, P. gingivalis stimulates Toll-like receptor-2 (TLR2) inside-out signaling which induces the high-affinity conformation of CR3. Although this activates CR3-dependent monocyte adhesion and transendothelial migration, P. gingivalis has co-opted this TLR2 proadhesive pathway for CR3 binding and intracellular entry. In CR3-deficient macrophages, the internalization of P. gingivalis is reduced twofold but its ability to survive intracellularly is reduced 1,000-fold, indicating that CR3 is exploited by the pathogen as a relatively safe portal of entry. The interaction of P. gingivalis fimbriae with CR3 additionally inhibits production of bioactive (p70) interleukin-12, which mediates immune clearance. In vivo blockade of CR3 leads to reduced persistence of P. gingivalis in the mouse host and diminished ability to cause periodontal bone loss, the hallmark of periodontal disease. Strikingly, the ability of P. gingivalis to interact with and exploit CR3 depends upon quantitatively minor components (FimCDE) of its fimbrial structure, which predominantly consists of polymerized fimbrillin (FimA). Indeed, isogenic mutants lacking FimCDE but expressing FimA are dramatically less persistent and virulent than the wildtype organism both in vitro and in vivo. This model of immune evasion through CR3 exploitation by P. gingivalis supports the concept that pathogens evolved to manipulate innate immune function for promoting their adaptive fitness.

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    • "Hajishengallis et al. have shown that the receptors involved in the inside-out proadhesive pathway (CD14, TLR2, and CD11b/CD18) are important for mediating Pg internalization within macrophages and also that Pg appears to proactively modulate beta2 integrin adhesive activity for intracellular uptake [14]. In addition, they have reported interaction of Pg with complement receptor-3 (CR3; CD11b/CD18) in monocytes/macrophages [15]. Previously, we have suggested the importance of beta2 integrin (CD11/CD18) as a cellular receptor of Pg fimbriae at the initiation stage of periodontal disease pathogenesis [16]. "
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    ABSTRACT: Porphyromonas gingivalis (Pg) fimbriae, in addition to lipopolysaccharide, are involved in the pathogenesis of periodontal disease. At the same time, bioactive compounds such as fibronectin (FN) and melatonin in saliva and gingival crevicular fluid have been reported to exert a preventive effect against periodontitis. Here, we review current knowledge regarding the potent inhibitory effects of FN and melatonin against Pg fimbria-induced induction of proinflammatory cytokines, cyclooxygenase-2 (COX-2) expression, and NF-kappa B activation in mouse macrophages and discuss their possible clinical application for prevention of periodontal diseases induced by oral bacteria.
    Full-text · Article · Apr 2012
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    • "These investigators also established that major fimbriae are immunostimulatory and the minor fimbriae are immunosuppressive and they proposed that the ability of P. gingivalis to uncouple dendritic cell maturation from the cytokine response could contribute to bacterial persistence. In addition, it is intriguing to postulate that P. gingivalis is trafficked to the atherosclerotic lesion via these immune cells including monocytes/macrophages or dendritic cells and that this may contribute to bacterial persistence in vivo (Fig. 3) (Hajishengallis et al., 2008b; Wang et al., 2007). "
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    ABSTRACT: A hallmark of infection with the gram-negative pathogen Porphyromonas gingivalis is the induction of a chronic inflammatory response. P. gingivalis induces a local chronic inflammatory response that results in oral inflammatory bone destruction, which manifests as periodontal disease. In addition to chronic inflammation at the initial site of infection, mounting evidence has accumulated supporting a role for P. gingivalis-mediated periodontal disease as a risk factor for several systemic diseases including, diabetes, preterm birth, stroke, and atherosclerotic cardiovascular disease. A growing number of in vitro studies have demonstrated that P. gingivalis infection stimulates cell activation commensurate with expected responses paralleling inflammatory atherosclerotic-type responses. Furthermore, various mouse models have been used to examine the ability of P. gingivalis to stimulate chronic inflammatory plaque accumulation and recent studies have pointed to a pivotal role for innate immune signaling via the Toll-like receptors in the chronic inflammation associated with P. gingivalis infection. In this review we discuss the pathogen and host cell specificity of these responses and discuss possible mechanisms by which this oral pathogen can induce and maintain a chronic state of inflammation at sites distant from oral infection.
    Preview · Article · Oct 2010
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    • "P. gingivalis fimbriae are recognized by TLR2 which then stimulates inside-out signaling to promote clustering of CR3, providing a safe and efficient entry pathway for the pathogen. This CR3 activation further leads to suppression of IL-12 production which would otherwise result from TLR2 activation of the phagocyte (Hajishengallis et al., 2008). Interestingly, P. gingivalis can degrade C5 to release a C5a-like fragment which is biologically active (Wingrove et al., 1992). "
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    ABSTRACT: The anaphylatoxin (AT) C3a, C5a and C5a-desArg are generally considered pro-inflammatory polypeptides generated after proteolytic cleavage of C3 and C5 in response to complement activation. Their well-appreciated effector functions include chemotaxis and activation of granulocytes, mast cells and macrophages. Recent evidence suggests that ATs are also generated locally within tissues by pathogen-, cell-, or contact system-derived proteases. This local generation of ATs is important for their pleiotropic biologic effects beyond inflammation. The ATs exert most of the biologic activities through ligation of three cognate receptors, i.e. the C3a receptor, the C5a receptor and the C5a receptor-like, C5L2. Here, we will discuss recent findings suggesting that ATs regulate cell apoptosis, lipid metabolism as well as innate and adaptive immune responses through their impact on antigen-presenting cells and T cells. As we will outline, such regulatory functions of ATs and their receptors play important roles in the pathogenesis of allergy, autoimmunity, neurodegenerative diseases, cancer and infections with intracellular pathogens.
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