Biology subjects

Cywes-Bentley, C.

Publications and source records attributed to Cywes-Bentley, C..

4 recordsLinked to original sources

bioRxiv2026

Persistent microbial material contributes to Alzheimer disease and is targetable by vaccination

Chronic neuroinflammation is increasingly recognized as a contributor to Alzheimer disease, yet the upstream stimuli that sustain it remain poorly defined. We investigated whether persistent microbial material contributes to Alzheimer disease using the conserved microbial polysaccharide poly-N-acetylglucosamine (PNAG). PNAG-containing microbial material colocalized with amyloid plaques in human Alzheimer disease brain tissue. In fully human neuronal and three-dimensional brain models, purified PNAG and PNAG-containing microbial vesicles activated Toll-like receptor 2-dependent inflammasome signaling and promoted amyloid-{beta} and phosphorylated tau accumulation. Vaccination targeting PNAG improved cognition, reduced glial activation and amyloid pathology, remodeled amyloid processing, and preserved gut microbial community structure in APP/PS1 mice. These findings identify persistent microbial material as an upstream contributor to Alzheimer disease-associated neuroinflammation and a potential therapeutic target.

neuroscience↗

bioRxiv2022

A high-throughput sequencing approach identifies immunotherapeutic targets for bacterial meningitis in neonates

BackgroundWorldwide, Escherichia coli is the leading cause of neonatal Gram-negative bacterial meningitis, but full understanding of the pathogenesis of this disease is not yet achieved. Moreover, to date, no vaccine is available against bacterial neonatal meningitis. MethodsHere, we used Transposon Sequencing of saturated banks of mutants (TnSeq) to evaluate E. coli K1 genetic fitness in murine neonatal meningitis. We identified E. coli K1 genes encoding for factors important for systemic dissemination and brain infection, and focused on products with a likely outer-membrane or extra-cellular localization, as these are potential vaccine candidates. We used in vitro and in vivo models to study the efficacy of active and passive immunization. ResultsWe selected for further study the conserved surface polysaccharide Poly-{beta}-(1-6)-N-Acetyl Glucosamine (PNAG), as a strong candidate for vaccine development. We found that PNAG was a virulence factor in our animal model. We showed that both passive and active immunization successfully prevented and/or treated meningitis caused by E. coli K1 in neonatal mice. We found an excellent opsonophagocytic killing activity of the antibodies to PNAG and in vitro these antibodies were also able to decrease binding, invasion and crossing of E. coli K1 through two blood brain barrier cell lines. Finally, to reinforce the potential of PNAG as a vaccine candidate in bacterial neonatal meningitis, we demonstrated that Group B Streptococcus, the main cause of neonatal meningitis in developed countries, also produced PNAG and that antibodies to PNAG could protect in vitro and in vivo against this major neonatal pathogen. InterpretationAltogether, these results indicate the utility of a high-throughput DNA sequencing method to identify potential immunotherapy targets for a pathogen, including in this study a potential broad-spectrum target for prevention of neonatal bacterial infections. FundingsANR Seq-N-Vaq, Charles Hood Foundation, Hearst Foundation. Groupe Pasteur Mutualite

microbiology↗

bioRxiv2021

Antibody Activities in Hyperimmune Plasma Against the Rhodococcus equi Virulence -Associated Protein A or Poly-N-Acetyl Glucosamine are Associated with Protection of Foals Against Rhodococcal Pneumonia

The efficacy of transfusion with hyperimmune plasma (HIP) for preventing pneumonia caused by Rhodococcus equi remains ill-defined. Quarter Horse foals at 2 large breeding farms were randomly assigned to be transfused with 2 L of HIP from adult donors hyperimmunized either with R. equi (RE HIP) or a conjugate vaccine eliciting antibody to the surface polysaccharide {beta}-1[->]6-poly-N-acetyl glucosamine (PNAG HIP) within 24 hours of birth. Antibody activities against PNAG and the rhodococcal virulence-associated protein A (VapA), and to deposition of complement component 1q (C1q) onto PNAG were determined by ELISA, and then associated with either clinical pneumonia at Farm A (n=119) or subclinical pneumonia at Farm B (n=114). Data were analyzed using multivariable logistic regression. Among RE HIP-transfused foals, the odds of pneumonia were approximately 6-fold higher (P = 0.0005) among foals with VapA antibody activity [≤] the population median. Among PNAG HIP-transfused foals, the odds of pneumonia were approximately 3-fold (P = 0.0347) and 11-fold (P = 0.0034) higher for foals with antibody activities [≤] the population median for PNAG or C1q deposition, respectively. Results indicated that levels of activity of antibodies against R. equi antigens are correlates of protection against both subclinical and clinical R. equi pneumonia in field settings. Among PNAG HIP-transfused foals, activity of antibodies with C1q deposition (an indicator of functional antibodies) were a stronger predictor of protection than was PNAG antibody activity alone. Collectively, these findings suggest that the amount and activity of antibodies in HIP (i.e., plasma volume and/or antibody activity) is positively associated with protection against R. equi pneumonia in foals.

immunology↗

bioRxiv2018

Antibody-based vaccine for TB: pre-clinical validation in horse foals challenged with the TB-related pathogen Rhodococcus equi

Immune correlates for protection against Mycobacterium tuberculosis (Mtb) infection and other intracellular pathogens are largely undetermined. Whether there is a role for antibody-mediated immunity is controversial. Rhodococcus equi is an intracellular pathogen causing severe pneumonia in young horse foals, eliciting a disease with many similarities to TB including intracellular residence, formation of granulomas and induction of severe respiratory distress. No purified vaccine antigens exist for R. equi or Mtb infections. Both express the microbial surface polysaccharide antigen poly-N-acetyl glucosamine (PNAG). Vaccination of pregnant mares with a synthetic PNAG oligosaccharide conjugated to tetanus toxoid elicited antibody that transferred to foals via colostrum and provided nearly complete protection against R. equi pneumonia in a randomized, controlled, blinded challenge trial. Infusion of PNAG-hyperimmune plasma protected 100% of foals against R. equi pneumonia. Vaccination induced opsonic antibodies that killed extracellular and intracellular R. equi and other intracellular pathogens. Killing of intracellular organisms was dependent on antibody recognition of surface expression of PNAG on infected macrophages, complement deposition and PMN-assisted lysis of infected macrophages. Protection also correlated with PBMC release of interferon-{gamma} in response to PNAG. Antibody-mediated opsonic killing and interferon-{gamma} release in response to PNAG may protect against disease caused by intracellular bacterial pathogens.

immunology↗