Abstract:Recent studies have highlighted the importance of the human microbiome in host health and disease. However, for the most part the mechanisms by which the microbiome mediates disease, or protection from it, remain poorly understood. The “keystone pathogen” hypothesis holds that certain low-abundance microbial pathogens can orchestrate inflammatory disease by remodelling a normally benign microbiota into a dysbiotic one. In this Opinion, we critically assess the available literature in support of this hypothesis… Show more
“…Identification of these virulence functions is compatible with the notion that pathogens can disturb microbial-host homeostasis and cause infections depending on the host and environmental conditions [10–12]. For example, P. gingivalis expresses gingipain cysteine proteinases that subvert host immune functions and promote dysbiosis, giving rise to claims that it is a ‘keystone’ pathogen [13]. On the other hand, S. mutans expresses specific types of glucosyltransferases for the production of a stable glucan biofilm scaffold from sucrose, which favours the assembly of three-dimensional acidic microenvironments within the biofilm matrix, and the emergence of aciduric and acidogenic species, which characterizes cariogenic biofilms [14].…”
We present an overview of how members of the oral microbiota respond to their environment by regulating gene expression through two-component signal transduction systems (TCSs) to support conditions compatible with homeostasis in oral biofilms or drive the equilibrium toward dysbiosis in response to environmental changes. Using studies on the sub-gingival Gram-negative anaerobe Porphyromonas gingivalis and Gram-positive streptococci as examples, we focus on the molecular mechanisms involved in activation of TCS and species specificities of TCS regulons.
“…Identification of these virulence functions is compatible with the notion that pathogens can disturb microbial-host homeostasis and cause infections depending on the host and environmental conditions [10–12]. For example, P. gingivalis expresses gingipain cysteine proteinases that subvert host immune functions and promote dysbiosis, giving rise to claims that it is a ‘keystone’ pathogen [13]. On the other hand, S. mutans expresses specific types of glucosyltransferases for the production of a stable glucan biofilm scaffold from sucrose, which favours the assembly of three-dimensional acidic microenvironments within the biofilm matrix, and the emergence of aciduric and acidogenic species, which characterizes cariogenic biofilms [14].…”
We present an overview of how members of the oral microbiota respond to their environment by regulating gene expression through two-component signal transduction systems (TCSs) to support conditions compatible with homeostasis in oral biofilms or drive the equilibrium toward dysbiosis in response to environmental changes. Using studies on the sub-gingival Gram-negative anaerobe Porphyromonas gingivalis and Gram-positive streptococci as examples, we focus on the molecular mechanisms involved in activation of TCS and species specificities of TCS regulons.
“…There is a strong correlation of contributions from oral pathogens in their development without specific understanding of the mechanisms leading to the disease pathogenesis. The focus of this review is on the periodontal keystone pathogen Porphyromonas gingivalis [1,2], and its secreted peptidyl arginine deiminase (PPAD) enzyme in the development of the extraoral autoimmune and inflammatory diseases mentioned above [3–7] (Figure 1). 10.1080/20002297.2018.1487742-F0001Figure 1.Schematic to show additive effect from an oral condition such as periodontitis to the development of mixed pathologies through smoking, atherosclerosis, and rheumatoid arthritis with direct inflammatory mediator input from P. gingivalis infection to Alzheimer’s disease.…”
Section: Introductionmentioning
confidence: 99%
“…P. gingivalis manipulates the host’s cellular immune responses and undermines host-microbe homeostasis [5], thereby leading to dysbiosis in a previously symbiotic microbiome [2]. Breakdown of cellular barriers allows dissemination of this pathogen to the rest of the body.…”
Periodontitis, rheumatoid arthritis (RA), atherosclerosis (AS), and Alzheimer’s disease (AD) are examples of complex human diseases with chronic inflammatory components in their etiologies. The initial trigger of inflammation that progresses to these diseases remains unresolved. Porphyromonas gingivalis is unique in its ability to secrete the P. gingivalis-derived peptidyl arginine deiminase (PPAD) and consequently offers a plausible and exclusive link to these diseases through enzymatic conversion of arginine to citrulline. Citrullination is a post-translational enzymatic modification of arginine residues in proteins formed as part of normal physiological processes. However, PPAD has the potential to modify self (bacterial) and host proteins by deimination of arginine amino acid residues, preferentially at the C-terminus. Migration of P. gingivalis and/or its secreted PPAD into the bloodstream opens up the possibility that this enzyme will citrullinate proteins at disparate body sites. Citrullination is associated with the pathogenesis of multifactorial diseases such as RA and AD, which have an elusive external perpetrator as they show epidemiological associations with periodontitis. Therefore, PPAD deserves some prominence as an external antigen, in at least, a subset of RA and AD cases, with as yet unidentified, immune/genetic vulnerabilities.
“…Porphyromonas gingivalis is considered to be a keystone Gram-negative, anaerobic intracellular pathogen in adult periodontitis [1]. It has a plethora of virulence factors [2] of which lipopolysaccharide (LPS), gingipains, fimbriae, hemagglutinins, and outer membrane vesicles (OMVs) are of major importance.…”
Lipopolysaccharide (LPS) of Porphyromonas gingivalis exists in at least two known forms, O-LPS and A-LPS. A-LPS shows heterogeneity in which two isoforms designated LPS1,435/1,449 and LPS1,690 appear responsible for tissue-specific immune signalling pathways activation and increased virulence. The modification of lipid A to tetra-acylated1,435/1,449 and/or penta-acylated1,690 fatty acids indicates poor growth conditions and bioavailability of hemin. Hemin protects P. gingivalis from serum resistance and the lipid A serves as a site for its binding. The LPS1,435/1,449 and LPS1,690 isoforms can produce opposite effects on the human Toll-like receptors (TLR) TLR2 and TLR4 activation. This enables P. gingivalis to select the conditions for its entry, survival, and that of its co-habiting species in the host, orchestrating its virulence to control innate immune pathway activation and biofilm dysbiosis. This review describes a number of effects that LPS1,435/1,449 and LPS1,690 can exert on the host tissues such as deregulation of the innate immune system, subversion of host cell autophagy, regulation of outer membrane vesicle production, and adverse effects on pregnancy outcome. The ability to change its LPS1,435/1,449 and/or LPS1,690 composition may enable P. gingivalis to paralyze local pro-inflammatory cytokine production, thereby gaining access to its primary location in periodontal tissue.
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