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  • 1
    Online Resource
    Online Resource
    DataSheet1.docx
    Frontiers Media SA ; 2024
    In:  Frontiers in Drug Delivery Vol. 4 ( 2024-4-26)
    Details
    In: Frontiers in Drug Delivery, Frontiers Media SA, Vol. 4 ( 2024-4-26)
    Abstract: Lipid nanoparticles (LNPs) have emerged as the platform of choice for mRNA delivery. Polyethylene glycol (PEG) is considered a key component of currently approved LNP-based delivery systems as it ensures particle stability and shapes various facets of LNP behavior in biological systems. Whilst PEG has numerous characteristics that are favorable for delivery systems, there is a growing body of evidence that suggests that it is immunogenic. Thus, next-generation mRNA therapeutics are likely to benefit from the identification of PEG alternatives. Towards this end, we have assessed the suitability of poly(2-methyl-2-oxazoline) (PMOZ) for LNP-based mRNA delivery. We compared the properties and bioactivities of PMOZ-containing LNPs to that of a standard composition that includes PEG. Decreasing the percentage of PMOZ in formulations improved transfection efficiency and enhanced the immunostimulatory potential. Reducing the PMOZ density was shown to enhanced antigen-specific T-cell responses in vivo . Interestingly, we found that this was not the case for antibody responses. A direct comparison between LNPs that contain the same amount of PEG or PMOZ strongly suggests that the former induces stronger CD8 + T-cell responses while the latter induces superior neutralizing titers. These findings augur well for the further development of PMOZ as a PEG replacement for LNP-based mRNA delivery approaches.
    Type of Medium: Online Resource
    ISSN: 2674-0850
    URL: Article
    URL: Article
    DOI: 10.3389/fddev.2024.1383038
    DOI: 10.3389/fddev.2024.1383038.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2024
    detail.hit.zdb_id: 3123813-0
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  • 2
    Online Resource
    Online Resource
    Quantitation of norovirus-specific IgG before and after infection in immunocompromised patients
    Springer Science and Business Media LLC ; 2020
    In:  Brazilian Journal of Microbiology Vol. 51, No. 1 ( 2020-03), p. 183-187
    Details
    In: Brazilian Journal of Microbiology, Springer Science and Business Media LLC, Vol. 51, No. 1 ( 2020-03), p. 183-187
    Type of Medium: Online Resource
    ISSN: 1517-8382 , 1678-4405
    URL: Article
    DOI: 10.1007/s42770-019-00176-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2017175-4
    SSG: 12
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  • 3
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    Online Resource
    A mass spectrometry guided approach for the identification of novel vaccine candidates in gram-negative pathogens
    Springer Science and Business Media LLC ; 2019
    In:  Scientific Reports Vol. 9, No. 1 ( 2019-11-22)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-11-22)
    Abstract: Vaccination is the most effective method to prevent infectious diseases. However, approaches to identify novel vaccine candidates are commonly laborious and protracted. While surface proteins are suitable vaccine candidates and can elicit antibacterial antibody responses, systematic approaches to define surfomes from gram-negatives have rarely been successful. Here we developed a combined discovery-driven mass spectrometry and computational strategy to identify bacterial vaccine candidates and validate their immunogenicity using a highly prevalent gram-negative pathogen, Helicobacter pylori , as a model organism. We efficiently isolated surface antigens by enzymatic cleavage, with a design of experiment based strategy to experimentally dissect cell surface-exposed from cytosolic proteins. From a total of 1,153 quantified bacterial proteins, we thereby identified 72 surface exposed antigens and further prioritized candidates by computational homology inference within and across species. We next tested candidate-specific immune responses. All candidates were recognized in sera from infected patients, and readily induced antibody responses after vaccination of mice. The candidate jhp_0775 induced specific B and T cell responses and significantly reduced colonization levels in mouse therapeutic vaccination studies. In infected humans, we further show that jhp_0775 is immunogenic and activates IFNγ secretion from peripheral CD4 + and CD8 + T cells. Our strategy provides a generic preclinical screening, selection and validation process for novel vaccine candidates against gram-negative bacteria, which could be employed to other gram-negative pathogens.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-019-53493-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2615211-3
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  • 4
    Online Resource
    Online Resource
    Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 8 ( 2013-02-19), p. 3047-3052
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 8 ( 2013-02-19), p. 3047-3052
    Abstract: Infection with the gastric bacterial pathogen Helicobacter pylori is typically contracted in early childhood and often persists for decades. The immunomodulatory properties of H. pylori that allow it to colonize humans persistently are believed to also account for H. pylori ’s protective effects against allergic and chronic inflammatory diseases. H. pylori infection efficiently reprograms dendritic cells (DCs) toward a tolerogenic phenotype and induces regulatory T cells (Tregs) with highly suppressive activity in models of allergen-induced asthma. We show here that two H. pylori virulence determinants, the γ-glutamyl transpeptidase GGT and the vacuolating cytotoxin VacA, contribute critically and nonredundantly to H. pylori ’s tolerizing effects on murine DCs in vitro and in vivo. The tolerance-promoting effects of both factors are independent of their described suppressive activity on T cells. Isogenic H. pylori mutants lacking either GGT or VacA are incapable of preventing LPS-induced DC maturation and fail to drive DC tolerization as assessed by induction of Treg properties in cocultured naive T cells. The Δ ggt and Δ vacA mutants colonize mice at significantly reduced levels, induce stronger T-helper 1 (Th1) and T-helper 17 (Th17) responses, and/or trigger more severe gastric pathology. Both factors promote the efficient induction of Tregs in vivo, and VacA is required to prevent allergen-induced asthma. The defects of the Δ ggt mutant in vitro and in vivo are phenocopied by pharmacological inhibition of the transpeptidase activity of GGT in all readouts. In conclusion, our results reveal the molecular players and mechanistic basis for H. pylori -induced immunomodulation, promoting persistent infection and conferring protection against allergic asthma.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1211248110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Helicobacter pylori Exploits the NLRC4 Inflammasome to Dampen Host Defenses
    The American Association of Immunologists ; 2019
    In:  The Journal of Immunology Vol. 203, No. 8 ( 2019-10-15), p. 2183-2193
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 203, No. 8 ( 2019-10-15), p. 2183-2193
    Abstract: Helicobacter pylori colonizes the stomach of around 50% of humans. This chronic infection can lead to gastric pathologic conditions such as gastric ulcers and gastric adenocarcinomas. The strong inflammatory response elicited by H. pylori is characterized by the induction of the expression of several cytokines. Among those, IL-18 is found highly upregulated in infected individuals, and its expression correlates with the severity of gastric inflammation. IL-18 is produced as inactive proform and has to be cleaved by the multiprotein complex inflammasome to be active. In immune cells, the NLRC4 inflammasome, which is activated by flagellin or bacterial secretion systems, was shown to be dispensable for H. pylori–induced inflammasome activation. However, apart from immune cells, gastric epithelial cells can also produce IL-18. In this study, we analyzed the role of the NLRC4 inflammasome during H. pylori infection. Our results indicate that NLRC4 and a functional type IV secretion system are crucial for the production of IL-18 from human and murine gastric epithelial cells. In vivo, Nlrc4−/− mice failed to produce gastric IL-18 upon H. pylori infection. Compared with wild type mice, Nlrc4−/− mice controlled H. pylori better without showing strong inflammation. Moreover, H. pylori–induced IL-18 inhibits β-defensin 1 expression in a NF-κB–dependent manner, resulting in higher bacterial colonization. At the same time, inflammasome activation enhances neutrophil infiltration, resulting in inflammation. Thus, NLRC4 inflammasome activation and subsequent IL-18 production favors bacterial persistence by inhibiting antimicrobial peptide production and, at the same time, contributes to gastric inflammation.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1900351
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 1475085-5
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  • 6
    Online Resource
    Online Resource
    Helicobacter pylori γ-Glutamyltranspeptidase Induces Tolerogenic Human Dendritic Cells by Activation of Glutamate Receptors
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 10 ( 2016-05-15), p. 4246-4252
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 10 ( 2016-05-15), p. 4246-4252
    Abstract: Helicobacter pylori infection is characterized by chronic persistence of the bacterium. Different virulence factors, including H. pylori γ-glutamyltranspeptidase (gGT), have been reported to induce tolerogenicity by reprogramming dendritic cells (DCs). gGT is present in all bacterial isolates, indicating an important role for gGT in the course of infection. In the current study, we have analyzed the effect of H. pylori gGT on human DCs and the subsequent adaptive immune response. We show that glutamate produced due to H. pylori gGT enzymatic activity tolerizes DCs by inhibiting cAMP signaling and dampening IL-6 secretion in response to the infection. Together, our results provide a novel molecular mechanism by which H. pylori manipulates the host’s immune response to persist within its host.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1501062
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
    detail.hit.zdb_id: 1475085-5
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  • 7
    Online Resource
    Online Resource
    Helicobacter pylori –Induced IL-1β Secretion in Innate Immune Cells Is Regulated by the NLRP3 Inflammasome and Requires the Cag Pathogenicity Island
    The American Association of Immunologists ; 2014
    In:  The Journal of Immunology Vol. 193, No. 7 ( 2014-10-01), p. 3566-3576
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 193, No. 7 ( 2014-10-01), p. 3566-3576
    Abstract: Infection with the gram-negative bacterium Helicobacter pylori is the most prevalent chronic bacterial infection, affecting ∼50% of the world’s population, and is the main risk factor of gastric cancer. The proinflammatory cytokine IL-1β plays a crucial role in the development of gastric tumors and polymorphisms in the IL-1 gene cluster leading to increased IL-1β production have been associated with increased risk for gastric cancer. To be active, pro–IL-1β must be cleaved by the inflammasome, an intracellular multiprotein complex implicated in physiological and pathological inflammation. Recently, H. pylori was postulated to activate the inflammasome in murine bone marrow–derived dendritic cells; however, the molecular mechanisms as well as the bacterial virulence factor acting as signal 2 activating the inflammasome remain elusive. In this study, we analyzed the inflammasome complex regulating IL-1β upon H. pylori infection as well as the molecular mechanisms involved. Our results indicate that H. pylori–induced IL-1β secretion is mediated by activation of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain–containing 3 inflammasome. We also show that reactive oxygen species, potassium efflux, and lysosomal destabilization are the main cellular mechanisms responsible of nucleotide-binding oligomerization domain family, pyrin domain–containing 3 inflammasome activation upon H. pylori infection, and identify vacuolating cytotoxin A and cag pathogenicity island as the bacterial virulence determinants involved. Moreover, in vivo experiments indicate an important role for the inflammasome in the onset and establishment of H. pylori infection and in the subsequent inflammatory response of the host.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1400362
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2014
    detail.hit.zdb_id: 1475085-5
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