Biology subjects

Barron, A. E.

Publications and source records attributed to Barron, A. E..

5 recordsLinked to original sources

bioRxiv2025

Identification of gingipains in glioblastoma tumors and evidence that P. gingivalis infection drives IL-6 and PD-L1 expression in glioma cells

Glioblastoma multiforme (GBM), a highly aggressive brain tumor that accounts for approximately 60% of all gliomas and 48% of primary central nervous system malignancies, is incurable and poorly understood, with a median survival of only 15 months after diagnosis. Thus, there is an urgent need to understand GBM pathogenesis in order to develop an effective treatment. Recent research has revealed frequent Alzheimers disease (AD) pathology in the brains of patients with GBM, i.e., amyloid beta (A{beta}) and hyperphosphorylated tau (pTau), indicating that GBM and AD may share some unknown environmental risk. Since chronic periodontitis (CP), and specifically Porphyromonas gingivalis (P. gingivalis), a keystone bacterial pathogen in CP, have emerged as risk factors for both AD and GBM, we investigated whether P. gingivalis gingipain virulence factors could be identified in GBM tissue samples and whether P. gingivalis infection affects glioma cell behavior. Using immunohistochemistry on tissue microarrays (70 GBM cores from 35 patients; 34 cerebral tissue cores from 17 patients), we quantified the presence of arginine-gingipain B (RgpB) and lysine-gingipain (Kgp) antigens. Both gingipains showed significantly elevated staining in GBM samples compared to controls (**p < .01, ****p < .0001, respectively), with Kgp levels notably higher than RgpB within GBM tissue (****p < .0001). In functional assays using U251 glioma cells, P. gingivalis infection induced robust, dose-dependent IL-6 secretion (peaking at MOI 5), increased PD-L1 expression by 30% (*p = .036), and significantly enhanced cell invasiveness (**p < .01) in a viability-dependent manner. These findings demonstrate that P. gingivalis gingipains are present at elevated levels in GBM tissue and that P. gingivalis infection reprograms glioma cells to adopt an immunosuppressive, invasive phenotype through upregulation of the IL-6/PD-L1 axis, suggesting a potential microbial contribution to GBM pathogenesis and immune evasion. Key pointsO_LIGlioblastoma multiforme (GBM) patients have frequent Alzheimers disease (AD) neuropathological changes in the tumor-adjacent cortex, indicating that GBM tumors may share some environmental risk factors with AD. C_LIO_LIThis study identifies gingipain antigens in GBM tissue samples at significantly elevated levels compared to healthy controls, suggesting that P. gingivalis infection may be an environmental risk factor for both AD and GBM. C_LIO_LIIn in vitro experiments, P. gingivalis infection of the human glioma cell line U251 upregulated IL-6 secretion and PD-L1 expression, and significantly increased cell invasiveness compared to uninfected cells. C_LI

neuroscience↗

bioRxiv2025

Targeting intracellular of populations Pseudomonas aeruginosa with peptide-mimetic therapies: individual efficacy and synergistic rescue of obsolete antibiotics.

Pseudomonas aeruginosa is a leading cause of human infections, with current treatment options severely limited by high levels of antimicrobial resistance. Historically considered to be an extracellular pathogen, recent evidence has emerged that P. aeruginosa is able to survive and replicate within human cells. These intracellular niches present an additional clinical challenge and may serve as bacterial reservoirs associated with chronic infections that are particularly difficult to eradicate. Here we describe the application of a novel peptide-based therapeutic against recalcitrant populations of bacteria residing within lung epithelial cells. This antimicrobial "peptoid" is able to target intracellular bacteria without harming host cells. In addition, we have shown that peptoid TM5 exhibits synergy with three antibiotics that otherwise have low efficacy against P. aeruginosa, effectively rescuing drugs that have become clinically obsolete. These synergistic combination therapies are also capable of reducing intracellular bacterial reservoirs, opening the door for potential new strategies against chronic P. aeruginosa infections.

microbiology↗

bioRxiv2025

Time-resolved phenotyping at subcellular resolution reveals shared principles and key trade-offs across antimicrobial peptide activities

Cationic antimicrobial peptides are a broad family of host defense molecules that neutralize bacteria by permeabilizing one or more membranes and/or inhibiting intracellular targets. Here, we present a time-resolved single-cell pipeline for quantifying these effects in Escherichia coli. Applying this pipeline to 18 diverse natural peptides and synthetic peptidomimetics reveals shared core activities, but with different kinetics, defining two classes with opposite trade-offs. Class I peptides cause abrupt growth arrest, predominantly coupled with inner membrane permeabilization and ribosome/DNA reorganization, conferring fast, multipronged action. However, rapid intracellular absorption by the first permeabilized cells depletes the extracellular pool, rendering them ineffective against dense populations, including biofilms. Class II peptides act more gradually, with delayed or absent inner membrane permeabilization, limiting their speed of action. However, this results in slower intracellular absorption and greater efficacy at high cell densities and against biofilms. These opposing functional trade-offs point to important immunological and therapeutic implications.

microbiology↗

bioRxiv2024

Pf bacteriophages hinder sputum antibiotic diffusion via electrostatic binding

Despite great progress in the field, chronic Pseudomonas aeruginosa (Pa) infections remain a major cause of morbidity and mortality in patients with cystic fibrosis, necessitating treatment with inhaled antibiotics. Pf phage is a filamentous bacteriophage produced by Pa that has been reported to act as a structural element in Pa biofilms. Pf presence has been associated with resistance to antibiotics and poor outcomes in cystic fibrosis, though the underlying mechanisms are unclear. Here, we have investigated how Pf phages and sputum biopolymers impede antibiotic diffusion using human sputum samples and fluorescent recovery after photobleaching. We demonstrate that tobramycin interacts with Pf phages and sputum polymers through electrostatic interactions. We also developed a set of mathematical models to analyze the complex observations. Our analysis suggests that Pf phages in sputum reduce the diffusion of charged antibiotics due to a greater binding constant associated with organized liquid crystalline structures formed between Pf phages and sputum polymers. This study provides insights into antibiotic tolerance mechanisms in chronic Pa infections and may offer potential strategies for novel therapeutic approaches. TeaserPf phages and sputum polymers reduce antibiotic diffusion via electrostatic interactions and liquid crystal formation.

microbiology↗

bioRxiv2023

Peptide-mimetic treatment of Pseudomonas aeruginosa in a mouse model of respiratory infection

The rise of drug resistance has become a global crisis, with >1 million deaths due to resistant bacterial infections each year. Pseudomonas aeruginosa, in particular, remains a serious problem with limited solutions due to complex resistance mechanisms that now lead to more than 32,000 multidrug-resistant (MDR) infections and over 2,000 deaths annually. While the emergence of resistant bacteria has become concerningly common, identification of useful new drug classes has been limited over the past 40+ years. We found that a potential novel therapeutic, the peptide-mimetic TM5, is effective at killing P. aeruginosa and displays sufficiently low toxicity for mammalian cells to allow for use in treatment of infections. Interestingly, TM5 kills P. aeruginosa more rapidly than traditional antibiotics, within 30-60 minutes in vitro, and is effective against a range of clinical isolates. In vivo, TM5 significantly reduced bacterial load in the lungs within 24 hours compared to untreated mice and demonstrated few adverse effects. Taken together, these observations suggest that TM5 shows promise as an alternative therapy for MDR P. aeruginosa respiratory infections.

microbiology↗