Porphyromonas gingivalis innate immune evasion contributes to site-specific chronic inflammation

Several successful pathogens evade host defenses resulting in the establishment of persistent and chronic infections. One such pathogen, Porphyromonas gingivalis, induces chronic low-grade inflammation associated with local inflammatory oral bone loss and systemic inflammation manifested as atherosclerosis. The pathogenic mechanisms contributing to P. gingivalis evasion of host immunity and chronic inflammation are not well defined. P. gingivalis evades host immunity at Toll-like receptor (TLR)-4 through expression of an atypical lipopolysaccharide (LPS) that contains lipid A species that exhibit TLR4 agonist or antagonist activity or fail to activate TLR4. By utilizing a series of P. gingivalis lipid A mutants we demonstrated that expression of antagonist lipid A structures resulted in weak induction of proinflammatory mediators. Moreover, expression of antagonist lipid A failed to activate the inflammasome, which correlated with increased bacterial survival in macrophages. Oral infection of atherosclerotic prone apolipoprotein E (ApoE) deficient mice with the antagonist lipid A strain resulted in vascular inflammation characterized by macrophage accumulation and atherosclerosis progression. In contrast, a P. gingivalis strain expressing exclusively agonist lipid A augmented levels of proinflammatory mediators and activated the inflammasome in a caspase-11 dependent manner, resulting in host cell lysis and decreased bacterial survival. ApoE deficient mice infected with the agonist lipid A strain exhibited diminished vascular inflammation. Notably, the ability of P. gingivalis to induce local inflammatory oral bone loss was independent of lipid A expression, indicative of distinct mechanisms for induction of local versus systemic inflammation by this pathogen. We next investigated the role of TLRs and lipid A on bacterial trafficking by the autophagic pathway. Originally characterized as a cell autonomous pathway for recycling damaged organelles and proteins, autophagy is now recognized to play a critical role in innate defense and release of the proinflammatory cytokine interleukin (IL)-1β. We demonstrated that P. gingivalis suppresses the autophagic pathway in macrophages for pathogen survival and intercepts autophagy-mediated IL-1β release. P. gingivalis-mediated suppression of autophagy was independent of lipid A expression but partially dependent on TLR2 signaling. Collectively, our results indicate that P. gingivalis evasion of innate immunity plays a role in chronic inflammation

Distinct gene signatures in aortic tissue from ApoE-/- mice exposed to pathogens or Western diet

BACKGROUND: Atherosclerosis is a progressive disease characterized by inflammation and accumulation of lipids in vascular tissue. Porphyromonas gingivalis (Pg) and Chlamydia pneumoniae (Cp) are associated with inflammatory atherosclerosis in humans. Similar to endogenous mediators arising from excessive dietary lipids, these Gram-negative pathogens are pro-atherogenic in animal models, although the specific inflammatory/atherogenic pathways induced by these stimuli are not well defined. In this study, we identified gene expression profiles that characterize P. gingivalis, C. pneumoniae, and Western diet (WD) at acute and chronic time points in aortas of Apolipoprotein E (ApoE-/-) mice. RESULTS: At the chronic time point, we observed that P. gingivalis was associated with a high number of unique differentially expressed genes compared to C. pneumoniae or WD. For the top 500 differentially expressed genes unique to each group, we observed a high percentage (76%) that exhibited decreased expression in P. gingivalis-treated mice in contrast to a high percentage (96%) that exhibited increased expression in WD mice. C. pneumoniae treatment resulted in approximately equal numbers of genes that exhibited increased and decreased expression. Gene Set Enrichment Analysis (GSEA) revealed distinct stimuli-associated phenotypes, including decreased expression of mitochondrion, glucose metabolism, and PPAR pathways in response to P. gingivalis but increased expression of mitochondrion, lipid metabolism, carbohydrate and amino acid metabolism, and PPAR pathways in response to C. pneumoniae; WD was associated with increased expression of immune and inflammatory pathways. DAVID analysis of gene clusters identified by two-way ANOVA at acute and chronic time points revealed a set of core genes that exhibited altered expression during the natural progression of atherosclerosis in ApoE-/- mice; these changes were enhanced in P. gingivalis-treated mice but attenuated in C. pneumoniae-treated mice. Notable differences in the expression of genes associated with unstable plaques were also observed among the three pro-atherogenic stimuli. CONCLUSIONS: Despite the common outcome of P. gingivalis, C. pneumoniae, and WD on the induction of vascular inflammation and atherosclerosis, distinct gene signatures and pathways unique to each pro-atherogenic stimulus were identified. Our results suggest that pathogen exposure results in dysregulated cellular responses that may impact plaque progression and regression pathways

Cognitive And Usability Issues In Geovisualization

We provide a research agenda for the International Cartographic Association's Commission on Visualization and Virtual Environment working group on Cognitive and Usability Issues in Geovisualization. Developments in hardware and software have led to (and will continue to stimulate) novel methods for visualizing geospatial data. It is our belief that these novel methods will be of little use if they are not developed within a theoretical cognitive framework and iteratively tested using usability engineering principles. We argue that cognitive and usability issues should be considered in the context of six major research themes: 1) geospatial virtual environments (GeoVEs), 2) dynamic representations (including animated and interactive maps), 3) metaphors and schemata in user interface design, 4) individual and group differences, 5) collaborative geovisualization, and 6) evaluating the effectiveness of geovisualization methods. A key point underlying our use of theoretical cognitive principles is that traditional cognitive theory for static 2D maps may not be applicable to interactive 3D immersive GeoVEs and dynamic representations thus new cognitive theory may need to be developed. Usability engineering extends beyond the traditional cartographic practice of user testing by evaluating software effectiveness throughout a lifecycle (including design, development, and deployment). Applying usability engineering to geovisualization, however, may be problematic because of the novelty of geovisualization and the associated difficulty of defining the nature of users and their tasks. Tackling the research themes is likely to require an interdisciplinary effort involving geographic information scientists, cognitive scientists, usability engineers, computer scient..

Reducing Opioid Consumption in Postoperative Renal Transplant Patients: A Retrospective Analysis

Background: Opioid use is high in renal transplant patients, both before and after surgery, in part due to the chronic pain associated with end-stage renal disease. Recent studies have shown patients with high opioid consumption post-transplant have higher incidences of graft loss and mortality. Despite this, opioids remain the mainstay of postoperative analgesia. Aims and Objectives: We wanted to see if known analgesic adjuncts, namely regional anesthesia via a continuous transversus abdominis plane (TAP) catheter block or systemic intravenous lidocaine, could reduce the postoperative opioid requirement in this patient group. Materials and Methods: We conducted a retrospective analysis of renal transplant patients over a 2-year period, comparing patients who had an opioid patient-controlled analgesia pump as their main treatment modality, against patients who had either a TAP block or systemic lidocaine as an adjunct. As a primary outcome measure, we calculated their oral morphine equivalents for the 72 hours post-transplant. We excluded patients who had surgical complications, or were on chronic opioid therapy for other conditions. Results: We identified 86 patients over this study period. We found that regional anesthesia was associated with a 34.4% reduction (P \u3c 0.01) and systemic lidocaine with a 36.5% reduction (P = 0.134) in cumulative opioid consumption without adversely affecting the quality of pain control. No significant complications were noted. Conclusion: Both regional anesthesia and systemic lidocaine are viable opioid sparing adjuncts for postoperative acute pain in this patient population

Distinct Lipid A Moieties Contribute to Pathogen-Induced Site-Specific Vascular Inflammation

<div><p>Several successful pathogens have evolved mechanisms to evade host defense, resulting in the establishment of persistent and chronic infections. One such pathogen, <i>Porphyromonas gingivalis</i>, induces chronic low-grade inflammation associated with local inflammatory bone loss and systemic inflammation manifested as atherosclerosis. <i>P. gingivalis</i> expresses an atypical lipopolysaccharide (LPS) structure containing heterogeneous lipid A species, that exhibit Toll-like receptor-4 (TLR4) agonist or antagonist activity, or are non-activating at TLR4. In this study, we utilized a series of <i>P. gingivalis</i> lipid A mutants to demonstrate that antagonistic lipid A structures enable the pathogen to evade TLR4-mediated bactericidal activity in macrophages resulting in systemic inflammation. Production of antagonistic lipid A was associated with the induction of low levels of TLR4-dependent proinflammatory mediators, failed activation of the inflammasome and increased bacterial survival in macrophages. Oral infection of ApoE^−/− mice with the <i>P. gingivalis</i> strain expressing antagonistic lipid A resulted in vascular inflammation, macrophage accumulation and atherosclerosis progression. In contrast, a <i>P. gingivalis</i> strain producing exclusively agonistic lipid A augmented levels of proinflammatory mediators and activated the inflammasome in a caspase-11-dependent manner, resulting in host cell lysis and decreased bacterial survival. ApoE^−/− mice infected with this strain exhibited diminished vascular inflammation, macrophage accumulation, and atherosclerosis progression. Notably, the ability of <i>P. gingivalis</i> to induce local inflammatory bone loss was independent of lipid A expression, indicative of distinct mechanisms for induction of local versus systemic inflammation by this pathogen. Collectively, our results point to a pivotal role for activation of the non-canonical inflammasome in <i>P. gingivalis</i> infection and demonstrate that <i>P. gingivalis</i> evades immune detection at TLR4 facilitating chronic inflammation in the vasculature. These studies support the emerging concept that pathogen-mediated chronic inflammatory disorders result from specific pathogen-mediated evasion strategies resulting in low-grade chronic inflammation.</p></div

Expression of immunologically silent or antagonistic lipid A structures exacerbates atherosclerotic plaque progression in the innominate artery.

<p>Innominate arteries of ApoE^−/− mice were imaged by MRA at baseline (wk 0) and at 8 and 16 wks after first oral infection. The temporal change in luminal area (mm²) was calculated for individual mice normalized to baseline luminal area (n = 10–12/group) (<b>A</b>). Sham-infected ApoE^−/− (<b>orange</b>); 381-infected ApoE^−/− (<b>black</b>); <i>PG1587</i>₃₈₁-infected ApoE^−/− (<b>blue</b>); <i>PG1773</i>₃₈₁- infected ApoE^−/− (<b>red</b>). <i>Inset</i> - the temporal change in luminal area calculated for individual mice normalized to 8 wk luminal area (n = 10–12/group). *p≤.01 **p<.001 ***p<.0001; two-tailed unpaired t-tests compared to sham-infected and <i>PG1587</i>₃₈₁-infected mice. (<b>B</b>) Representative images of the innominate artery with F4/80 staining (macrophages stain brown) and hematoxylin counterstaining for each group at 10× and 40× (n = 3/group) (See also <b><a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004215#ppat.1004215.s003" target="_blank">Figure S3</a></b>).</p