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    Investigation of halogenated furanones as inhibitors of quorum sensing-regulated bioluminescence in Vibrio harveyi
    (Future Science Group, 2023-03-17) Pinheiro, Jorge; Lyons, Thérèse; Las Heras, Vanessa; Recio, Miguel Villoria; Gahan, Cormac G. M.; O'Sullivan, Timothy P.
    Aim: Vibrio harveyi is a Gram-negative marine bacterium that is a model system in the study of quorum sensing (QS). V. harveyi uses multichannel QS, mediated by three signaling molecules. The aim of this study was to synthesize and screen a diverse series of furanones for their potential to inhibit V. harveyi quorum sensing. Materials & methods: A library of halogenated furanones was prepared and derivatized using standard Pd-mediated coupling reactions and subsequently evaluated for their effects on V. harveyi bioluminescence. Results & conclusion: Several furanones inhibited QS-regulated bioluminescence, with gem-dichlorofuranone and tribromofuranone compounds proving especially effective. Importantly, a number of compounds were effective inhibitors of V. harveyi bioluminescence but did not have an impact on bacterial growth.
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    Characterizing phage-host interactions in a simplified human intestinal barrier model
    (MDPI, 2020) Núñez-Sánchez, María A.; Colom, Joan; Walsh, Lauren; Buttimer, Colin; Bolocan, Andrei Sorin; Pang, Rory; Gahan, Cormac G.; Hill, Colin; Science Foundation Ireland; Johnson & Johnson Innovative Medicine; European Commission; Irish Research Council
    An intestinal epithelium model able to produce mucus was developed to provide an environment suitable for testing the therapeutic activity of gut bacteriophages. We show that Enterococcus faecalis adheres more effectively in the presence of mucus, can invade the intestinal epithelia and is able to translocate after damaging tight junctions. Furthermore, Enterococcus phage vB_EfaM_A2 (a member of Herelleviridae that possesses virion associated immunoglobin domains) was found to translocate through the epithelium in the presence and absence of its host bacteria. Phage A2 protected eukaryotic cells by reducing mortality and maintaining the structure of the cell layer structure. We suggest the mammalian cell model utilized within this study as an adaptable in vitro model that can be employed to enable a better understanding of phage–bacteria interactions and the protective impact of phage therapy relating to the intestinal epithelium.
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    The impact of fingolimod on Treg function in brain ischaemia
    (John Wiley and Sons Inc, 2023) Malone, Kyle; Shearer, Jennifer A.; Waeber, Christian; Moore, Anne C.; Irish Research Council; Health Research Board; European Regional Development Fund
    Fingolimod has generally shown neuroprotective effects in stroke models. Here, we tested the hypothesis that fingolimod modulates T-cell cytokine production towards a regulatory phenotype. Second, we investigated how fingolimod altered the Treg suppressive function and the sensitivity of effector T cells to regulation. Mice that had underwent the permanent electrocoagulation of the left middle cerebral artery received saline or fingolimod (0.5 mg/kg) daily for 10-days post-ischaemia. Fingolimod improved neurobehavioural recovery compared to saline control and increased Treg frequency in the periphery and brain. Tregs from fingolimod-treated animals had a higher expression of CCR8. Fingolimod increased the frequencies of CD4+ IL-10+ , CD4+ IFN-γ+ and CD4+ IL-10+ IFN-γ+ cells in spleen and blood, and CD4+ IL-17+ cells in the spleen, with only minor effects on CD8+ T-cell cytokine production. Treg from post-ischaemic mice had reduced suppressive function compared to Treg from non-ischaemic mice. Fingolimod treatment rescued this function against saline-treated but not fingolimod-treated CD4+ effector T cells. In conclusion, fingolimod seems to improve the suppressive function of Treg post-stroke while also increasing the resistance of CD4+ effector cells to this suppression. Fingolimod's capacity to increase both effector and regulatory functions may explain the lack of consistent improvement in functional recovery in experimental brain ischaemia.
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    Low adenovirus vaccine doses administered to skin using microneedle patches induce better functional antibody immunogenicity as compared to systemic injection
    (MDPI AG, 2021) Flynn, Olivia; Dillane, Kate; Lanza, Juliane S.; Marshall, Jennifer M.; Jin, Jing; Silk, Sarah E.; Draper, Simon J.; Moore, Anne C.; Health Research Board
    Adenovirus-based vaccines are demonstrating promising clinical potential for multiple infectious diseases, including COVID-19. However, the immunogenicity of the vector itself decreases its effectiveness as a boosting vaccine due to the induction of strong anti-vector neutralizing immunity. Here we determined how dissolvable microneedle patches (DMN) for skin immunization can overcome this issue, using a clinically-relevant adenovirus-based Plasmodium falciparum malaria vaccine, AdHu5–PfRH5, in mice. Incorporation of vaccine into patches significantly enhanced its thermostability compared to the liquid form. Conventional high dose repeated immunization by the intramuscular (IM) route induced low antigen-specific IgG titres and high anti-vector immunity. A low priming dose of vaccine, by the IM route, but more so using DMN patches, induced the most efficacious immune responses, assessed by parasite growth inhibitory activity (GIA) assays. Administration of low dose AdHu5–PfRH5 using patches to the skin, boosted by high dose IM, induced the highest antigen-specific serum IgG response after boosting, the greatest skewing of the antibody response towards the antigen and away from the vector, and the highest efficacy. This study therefore demonstrates that repeated use of the same adenovirus vaccine can be highly immunogenic towards the transgene if a low dose is used to prime the response. It also provides a method of stabilizing adenovirus vaccine, in easy-to-administer dissolvable microneedle patches, permitting storage and distribution out of cold chain.
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    Nebulised delivery of RNA formulations to the lungs: From aerosol to cytosol
    (Elsevier, 2024-11-25) Neary, Michael T.; Mulder, Lianne M.; Kowalski, Piotr S.; MacLoughlin, Ronan; Crean, Abina M.; Ryan, Katie B.; Science Foundation Ireland; Health Research Board; European Research Council; Irish Research Council
    In the past decade RNA-based therapies such as small interfering RNA (siRNA) and messenger RNA (mRNA) have emerged as new and ground-breaking therapeutic agents for the treatment and prevention of many conditions from viral infection to cancer. Most clinically approved RNA therapies are parenterally administered which impacts patient compliance and adds to healthcare costs. Pulmonary administration via inhalation is a non-invasive means to deliver RNA and offers an attractive alternative to injection. Nebulisation is a particularly appealing method due to the capacity to deliver large RNA doses during tidal breathing. In this review, we discuss the unique physiological barriers presented by the lung to efficient nebulised RNA delivery and approaches adopted to circumvent this problem. Additionally, the different types of nebulisers are evaluated from the perspective of their suitability for RNA delivery. Furthermore, we discuss recent preclinical studies involving nebulisation of RNA and analysis in in vitro and in vivo settings. Several studies have also demonstrated the importance of an effective delivery vector in RNA nebulisation therefore we assess the variety of lipid, polymeric and hybrid-based delivery systems utilised to date. We also consider the outlook for nebulised RNA medicinal products and the hurdles which must be overcome for successful clinical translation. In summary, nebulised RNA delivery has demonstrated promising potential for the treatment of several lung-related conditions such as asthma, COPD and cystic fibrosis, to which the mode of delivery is of crucial importance for clinical success.