scholarly journals Are Porphyromonas gingivalis Outer Membrane Vesicles Microbullets for Sporadic Alzheimer’s Disease Manifestation?

2018 ◽  
Vol 2 (1) ◽  
pp. 219-228 ◽  
Author(s):  
Sim K. Singhrao ◽  
Ingar Olsen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Outer Membrane ◽  
Porphyromonas Gingivalis ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Sporadic Alzheimer’S Disease ◽  
Disease Manifestation

scholarly journals Porphyromonas gingivalis Outer Membrane Vesicles as the Major Driver of and Explanation for Neuropathogenesis, the Cholinergic Hypothesis, Iron Dyshomeostasis, and Salivary Lactoferrin in Alzheimer’s Disease

2021 ◽  
pp. 1-34
Author(s):  
Peter L. Nara ◽  
Daniel Sindelar ◽  
Marc S. Penn ◽  
Jan Potempa ◽  
W. Sue T. Griffin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Outer Membrane ◽  
Porphyromonas Gingivalis ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Direct Role ◽  
Cholinergic Hypothesis ◽  
Genetic Mechanisms ◽  
The Brain

Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced “chronic” multi-systems inflammatory disease(s) including Alzheimer’s disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria’s direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the “infection hypothesis” of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of “Pg bacteria” residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the “Gingipains Hypothesis”, AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.

Metabolic Alterations in the Outer Membrane Vesicles of Patients with Alzheimer’s Disease: An LC-MS/MS-based Metabolomics Analysis

2020 ◽  
Vol 16 (13) ◽  
pp. 1183-1195 ◽  
Author(s):  
Shou-Chao Wei ◽  
Wei Wei ◽  
Wan-Juan Peng ◽  
Zhou Liu ◽  
Zhi-You Cai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Outer Membrane ◽  
Arachidic Acid ◽  
Membrane Vesicles ◽  
Leukotriene B4 ◽  
Outer Membrane Vesicles ◽  
Healthy Controls ◽  
Multivariate Statistical ◽  
Metabolomics Analysis

Objective: To characterize the specific metabolomics profiles in the outer membrane vesicles (OMVs) of patients with Alzheimer’s Disease (AD) and to explore potential metabolic biomarkers and their diagnostic roles. Methods: Nine AD patients and age- and sex-matched healthy controls were enrolled, and feces were collected. OMVs were extracted, purified, and then analyzed using liquid chromatography-tandem mass chromatography (LC-MS/MS) method coupled with a series of multivariate statistical analyses. Results: Remarkable differences were found between the OMVs from AD patients and those from healthy controls. A number of differential metabolites and several top-altered metabolic pathways were identified. The levels of aspartate, L-aspartate, imidazole-4-acetate and L-glutamate were confirmed to be highly upregulated in AD-OMVs. Other differential metabolites, such as arachidic acid, prostaglandin G2, and leukotriene B4, were also identified. Furthermore, the differential metabolites possessed higher areas under the ROC curve (AUCs). Conclusion: Metabolic activity is significantly altered in the OMVs from AD patients. This data might be helpful for identifying novel biomarkers and their diagnostic roles in AD. : Furthermore, OMVs metabolomics analysis combined with GWAS could enrich our understanding of the genetic spectrum of AD and lead to early predictions and diagnosis and clinical applications of better AD treatments.

scholarly journals Sphingolipid Containing Outer Membrane Vesicles Serve as a Delivery Vehicle to Limit Host Immune Response to Porphyromonas gingivalis

2020 ◽  
Author(s):  
Fernanda G. Rocha ◽  
Gregory Ottenberg ◽  
Zavier G. Eure ◽  
Mary E. Davey ◽  
Frank C. Gibson
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Outer Membrane ◽  
Porphyromonas Gingivalis ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Delivery Vehicle ◽  
Cellular Inflammatory Response ◽  
Elevated Expression ◽  
Host Inflammatory Response

ABSTRACTSphingolipids (SLs) are essential structural components of mammalian cell membranes. Our group recently determined that the oral anaerobe Porphyromonas gingivalis delivers its SLs to host cells, and that the ability of P. gingivalis to synthesize SLs limits the elicited host inflammatory response during cellular infection. As P. gingivalis robustly produces outer membrane vesicles (OMVs), we hypothesized that OMVs serve as a delivery vehicle for SLs, that the SL status of the OMVs may impact cargo loading to OMVs, and that SL-containing OMVs limit elicited host inflammation similar to that observed by direct bacterial challenge. Transwell cell culture experiments determined that in comparison to the parent strain W83, the SL-null mutant elicited a hyper-inflammatory immune response from THP-1 macrophage-like cells with elevated TNF-α, IL-1β, and IL-6. Targeted assessment of Toll-like receptors (TLRs) identified elevated expression of TLR2, unchanged TLR4, and elevated expression of the adaptor molecules MyD88 and TRIF by SL-null P. gingivalis. No significant differences in gingipain activity were observed in our infection models and both strains produced OMVs of similar size. Using comparative 2-dimensional gel electrophoresis we identified differences in the protein cargo of the OMVs between parent and SL-null strain. Importantly, use of purified OMVs recapitulated the cellular inflammatory response observed in the transwell system with whole bacteria. These findings provide new insights into the role of SLs in P. gingivalis OMV cargo assembly and expand our understanding of SL-OMVs as bacterial structures that modulate the host inflammatory response.

scholarly journals PPAD Activity Promotes Outer Membrane Vesicle Biogenesis and Surface Translocation by Porphyromonas gingivalis

2020 ◽  
Author(s):  
Danielle M. Vermilyea ◽  
M. Fata Moradali ◽  
Hey-Min Kim ◽  
Mary E. Davey
Keyword(s):  
Outer Membrane ◽  
Porphyromonas Gingivalis ◽  
Membrane Vesicle ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Virulence Determinants ◽  
Peptidylarginine Deiminase ◽  
Arginine Metabolism ◽  
Key Factor ◽  
Surface Translocation

Many bacteria switch between a sessile and a motile mode in response to environmental and host-related signals. Porphyromonas gingivalis, an oral anaerobe implicated in the etiology of chronic periodontal disease, has long been described as a non-motile bacterium. Yet, recent studies have shown that under certain conditions, P. gingivalis is capable of surface translocation. Considering these findings, this work aimed to increase our understanding as to how P. gingivalis transitions between sessile growth and surface migration. Here we show that the peptidylarginine deiminase secreted by P. gingivalis (PPAD), an enzyme previously shown to be upregulated during surface translocation and to constrain biofilm formation, promotes surface translocation. In the absence of PPAD, the production of outer membrane vesicles (OMVs) was drastically reduced. In turn, there was a reduction in gingipain-mediated proteolysis and a reduced zone of hydration around the site of inoculation. RNA-Seq and metabolomics analyses also showed that these changes corresponded to a shift in arginine metabolism. Overall, this study provides new evidence for the functional relevance of PPAD and proteases, as well as the importance of PPAD activity in OMV biogenesis and release. Our findings support the model that citrullination is a critical mechanism during lifestyle transition between surface-attached growth and surface translocation by modulating OMV-mediated proteolysis and arginine metabolism. IMPORTANCE Gram-negative bacteria produce nanosized OMVs that are actively released into their surroundings. The oral anaerobe P. gingivalis is prolific in OMV production and many of the proteins packaged in these vesicles are proteolytic or protein modifying enzymes. This includes key virulence determinants, such as the gingipains and PPAD (a unique peptidylarginine deiminase). Here, we show that PPAD activity (citrullination) is involved in OMV biogenesis. The study reveals an unusual mechanism that allows this bacterium to transform its surroundings. Since OMVs are detected in circulation and in systemic tissues, our study also supports the notion that PPAD activity may be a key factor in the correlation between periodontitis and systemic diseases further supporting PPAD as an important therapeutic target.

scholarly journals Citrullinome of Porphyromonas gingivalis Outer Membrane Vesicles: Confident Identification of Citrullinated Peptides

2019 ◽  
Vol 19 (1) ◽  
pp. 167-180 ◽  
Author(s):  
Daniel Nyberg Larsen ◽  
Christian Engelbrecht Mikkelsen ◽  
Mads Kierkegaard ◽  
Grzegorz P. Bereta ◽  
Zuzanna Nowakowska ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Porphyromonas Gingivalis ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles

An Investigation into the Effects of Outer Membrane Vesicles and Lipopolysaccharide of Porphyromonas gingivalis on Blood-Brain Barrier Integrity, Permeability, and Disruption of Scaffolding Proteins in a Human in vitro Model

2022 ◽  
pp. 1-22
Author(s):  
Anna Barlach Pritchard ◽  
Zsolt Fabian ◽  
Clare L. Lawrence ◽  
Glyn Morton ◽  
StJohn Crean ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Human Brain ◽  
Outer Membrane ◽  
Porphyromonas Gingivalis ◽  
Virulence Factors ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells

Background: The effects of the key pathogens and virulence factors associated with gum disease such as Porphyromonas gingivalis (P. gingivalis) on the central nervous system is of great interest with respect to development of neuropathologies and hence therapeutics and preventative strategies. Chronic infections and associated inflammation are known to weaken the first line of defense for the brain, the blood-brain barrier (BBB). Objective: The focus of this study is to utilize an established human in vitro BBB model to evaluate the effects of P. gingivalis virulence factors lipopolysaccharide (LPS) and outer membrane vesicles (OMVs) on a primary-derived human model representing the neurovascular unit of the BBB. Methods: Changes to the integrity of the BBB after application of P. gingivalis LPS and OMVs were investigated and correlated with transport of LPS. Additionally, the effect of P. gingivalis LPS and OMVs on human brain microvascular endothelial cells in monolayer was evaluated using immunofluorescence microscopy. Results: The integrity of the BBB model was weakened by application of P. gingivalis LPS and OMVs, as measured by a decrease in electrical resistance and a recovery deficit was seen in comparison to the controls. Application of P. gingivalis OMVs to a monoculture of human brain microvascular endothelial cells showed disruption of the tight junction zona occludens protein (ZO-1) compared to controls. Conclusion: These findings show that the integrity of tight junctions of the human BBB could be weakened by association with P. gingivalis virulence factors LPS and OMVs containing proteolytic enzymes (gingipains).

Sign in / Sign up

Export Citation Format

Share Document