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  1. Article ; Online: In Vitro Biophysical Characterization of Candidalysin: A Fungal Peptide Toxin.

    Lee, Sejeong / Kichik, Nessim / Hepworth, Olivia W / Richardson, Jonathan P / Naglik, Julian R

    Methods in molecular biology (Clifton, N.J.)

    2022  Volume 2542, Page(s) 163–176

    Abstract: In 2016, the first peptide toxin in any human fungal pathogen was identified. It was discovered in Candida albicans and was named candidalysin. Candidalysin is an amphipathic cationic peptide that damages cell membranes. Like most lytic peptides, ... ...

    Abstract In 2016, the first peptide toxin in any human fungal pathogen was identified. It was discovered in Candida albicans and was named candidalysin. Candidalysin is an amphipathic cationic peptide that damages cell membranes. Like most lytic peptides, candidalysin shows alpha-helical secondary structure. As the helicity and the membrane lytic activity of candidalysin are key factors for pathogenicity, here we describe in vitro approaches to monitor both its membrane-lytic function and the secondary structure. First, membrane permeabilization activity of candidalysin is measured in real time by direct electrical recording. Second, the secondary structure and helicity of candidalysin are determined by circular dichroism spectroscopy. These biophysical methods provide a means to characterize the activity and physical properties of candidalysin in vitro and will be useful in determining the structural and functional features of candidalysin and other similar cationic membrane-active peptides.
    MeSH term(s) Candida albicans/metabolism ; Circular Dichroism ; Fungal Proteins/metabolism ; Humans ; Mycotoxins/metabolism ; Peptides/metabolism ; Virulence
    Chemical Substances ECE1 protein, Candida albicans ; Fungal Proteins ; Mycotoxins ; Peptides
    Language English
    Publishing date 2022-08-25
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-2549-1_12
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Fungal melanin suppresses airway epithelial chemokine secretion through blockade of calcium fluxing.

    Reedy, Jennifer L / Jensen, Kirstine Nolling / Crossen, Arianne J / Basham, Kyle J / Ward, Rebecca A / Reardon, Christopher M / Harding, Hannah Brown / Hepworth, Olivia W / Simaku, Patricia / Kwaku, Geneva N / Tone, Kazuya / Willment, Janet A / Reid, Delyth M / Stappers, Mark H T / Brown, Gordon D / Rajagopal, Jayaraj / Vyas, Jatin M

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Respiratory infections caused by the human fungal ... ...

    Abstract Respiratory infections caused by the human fungal pathogen
    Language English
    Publishing date 2024-05-06
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.03.28.534632
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: BTK inhibitor-induced defects in human neutrophil effector activity against Aspergillus fumigatus are restored by TNFα.

    Vargas-Blanco, Diego A / Hepworth, Olivia W / Basham, Kyle J / Simaku, Patricia / Crossen, Arianne J / Timmer, Kyle D / Hopke, Alex / Brown Harding, Hannah / Vandal, Steven R / Jensen, Kirstine N / Floyd, Daniel J / Reedy, Jennifer L / Reardon, Christopher / Mansour, Michael K / Ward, Rebecca A / Irimia, Daniel / Abramson, Jeremy S / Vyas, Jatin M

    JCI insight

    2024  

    Abstract: Inhibition of Bruton's tyrosine kinase (BTK) through covalent modifications of its active site (e.g., ibrutinib [IBT]) is a preferred treatment for multiple B cell malignancies. However, IBT-treated patients are more susceptible to invasive fungal ... ...

    Abstract Inhibition of Bruton's tyrosine kinase (BTK) through covalent modifications of its active site (e.g., ibrutinib [IBT]) is a preferred treatment for multiple B cell malignancies. However, IBT-treated patients are more susceptible to invasive fungal infections, although the mechanism is poorly understood. Neutrophils are the primary line of defense against these infections; therefore, we examined the impact of IBT on primary human neutrophil effector activity against Aspergillus fumigatus. IBT significantly impaired the ability of neutrophils to kill A. fumigatus and potently inhibited reactive oxygen species (ROS) production, chemotaxis, and phagocytosis. Importantly, exogenous TNFα fully compensated for defects imposed by IBT and newer-generation BTK inhibitors and restored the ability of neutrophils to contain A. fumigatus hyphal growth. Blocking TNFα did not impact ROS production in healthy neutrophils but prevented exogenous TNFα from rescuing the phenotype of IBT-treated neutrophils. The restorative capacity of TNFα was independent of transcription. Moreover, the addition of TNFα immediately rescued ROS production in IBT-treated neutrophils indicating that TNFα worked through a BTK-independent signaling pathway. Finally, TNFα restored effector activity of primary neutrophils from patients on IBT therapy. Altogether, our data indicate that TNFα rescues the antifungal immunity block imposed by inhibition of BTK in primary human neutrophils.
    Language English
    Publishing date 2024-05-07
    Publishing country United States
    Document type Journal Article
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.176162
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Receptor-kinase EGFR-MAPK adaptor proteins mediate the epithelial response to Candida albicans via the cytolytic peptide toxin, candidalysin.

    Ponde, Nicole O / Lortal, Léa / Tsavou, Antzela / Hepworth, Olivia W / Wickramasinghe, Don N / Ho, Jemima / Richardson, Jonathan P / Moyes, David L / Gaffen, Sarah L / Naglik, Julian R

    The Journal of biological chemistry

    2022  Volume 298, Issue 10, Page(s) 102419

    Abstract: Candida albicans (C. albicans) is a dimorphic commensal human fungal pathogen that can cause severe oropharyngeal candidiasis (oral thrush) in susceptible hosts. During invasive infection, C. albicans hyphae invade oral epithelial cells (OECs) and ... ...

    Abstract Candida albicans (C. albicans) is a dimorphic commensal human fungal pathogen that can cause severe oropharyngeal candidiasis (oral thrush) in susceptible hosts. During invasive infection, C. albicans hyphae invade oral epithelial cells (OECs) and secrete candidalysin, a pore-forming cytolytic peptide that is required for C. albicans pathogenesis at mucosal surfaces. Candidalysin is produced in the hyphal invasion pocket and triggers cell damage responses in OECs. Candidalysin also activates multiple MAPK-based signaling events that collectively drive the production of downstream inflammatory mediators that coordinate downstream innate and adaptive immune responses. The activities of candidalysin are dependent on signaling through the epidermal growth factor receptor (EGFR). Here, we interrogated known EGFR-MAPK signaling intermediates for their roles mediating the OEC response to C. albicans infection. Using RNA silencing and pharmacological inhibition, we identified five key adaptors, including growth factor receptor-bound protein 2 (Grb2), Grb2-associated binding protein 1 (Gab1), Src homology and collagen (Shc), SH2-containing protein tyrosine phosphatase-2 (Shp2), and casitas B-lineage lymphoma (c-Cbl). We determined that all of these signaling effectors were inducibly phosphorylated in response to C. albicans. These phosphorylation events occurred in a candidalysin-dependent manner and additionally required EGFR phosphorylation, matrix metalloproteinases (MMPs), and cellular calcium flux to activate a complete OEC response to fungal infection. Of these, Gab1, Grb2, and Shp2 were the dominant drivers of ERK1/2 activation and the subsequent production of downstream innate-acting cytokines. Together, these results identify the key adaptor proteins that drive the EGFR signaling mechanisms that underlie oral epithelial responses to C. albicans.
    MeSH term(s) Humans ; Candida albicans/metabolism ; Candida albicans/pathogenicity ; Cytokines/metabolism ; ErbB Receptors/metabolism ; Fungal Proteins/metabolism ; Shc Signaling Adaptor Proteins/metabolism ; Candidiasis, Oral/metabolism ; Candidiasis, Oral/microbiology ; Mouth Mucosa/metabolism ; Mouth Mucosa/microbiology ; Epithelial Cells/metabolism ; Epithelial Cells/microbiology
    Chemical Substances Cytokines ; ECE1 protein, Candida albicans ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Fungal Proteins ; Shc Signaling Adaptor Proteins
    Language English
    Publishing date 2022-08-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2022.102419
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Candidalysins Are a New Family of Cytolytic Fungal Peptide Toxins.

    Richardson, Jonathan P / Brown, Rhys / Kichik, Nessim / Lee, Sejeong / Priest, Emily / Mogavero, Selene / Maufrais, Corinne / Wickramasinghe, Don N / Tsavou, Antzela / Kotowicz, Natalia K / Hepworth, Olivia W / Gallego-Cortés, Ana / Ponde, Nicole O / Ho, Jemima / Moyes, David L / Wilson, Duncan / D'Enfert, Christophe / Hube, Bernhard / Naglik, Julian R

    mBio

    2022  Volume 13, Issue 1, Page(s) e0351021

    Abstract: Candidalysin is the first cytolytic peptide toxin identified in any human fungal pathogen. Candidalysin is secreted by Candida albicans and is critical for driving infection and host immune responses in several model systems. However, ...

    Abstract Candidalysin is the first cytolytic peptide toxin identified in any human fungal pathogen. Candidalysin is secreted by Candida albicans and is critical for driving infection and host immune responses in several model systems. However,
    MeSH term(s) Humans ; Mycotoxins ; Calcium/metabolism ; Fungal Proteins/metabolism ; Candida albicans/metabolism ; Candida tropicalis ; Peptides/metabolism ; Cytokines/metabolism
    Chemical Substances ECE1 protein, Candida albicans ; Mycotoxins ; Calcium (SY7Q814VUP) ; Fungal Proteins ; Peptides ; Cytokines
    Language English
    Publishing date 2022-01-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2557172-2
    ISSN 2150-7511 ; 2161-2129
    ISSN (online) 2150-7511
    ISSN 2161-2129
    DOI 10.1128/mbio.03510-21
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: IL-36 and IL-1/IL-17 Drive Immunity to Oral Candidiasis via Parallel Mechanisms.

    Verma, Akash H / Zafar, Hanna / Ponde, Nicole O / Hepworth, Olivia W / Sihra, Diksha / Aggor, Felix E Y / Ainscough, Joseph S / Ho, Jemima / Richardson, Jonathan P / Coleman, Bianca M / Hube, Bernhard / Stacey, Martin / McGeachy, Mandy J / Naglik, Julian R / Gaffen, Sarah L / Moyes, David L

    Journal of immunology (Baltimore, Md. : 1950)

    2018  Volume 201, Issue 2, Page(s) 627–634

    Abstract: Protection against microbial infection by the induction of inflammation is a key function of the IL-1 superfamily, including both classical IL-1 and the new IL-36 cytokine families. ...

    Abstract Protection against microbial infection by the induction of inflammation is a key function of the IL-1 superfamily, including both classical IL-1 and the new IL-36 cytokine families.
    MeSH term(s) Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Candida albicans/immunology ; Candidiasis/immunology ; Cell Line ; Fungal Proteins/metabolism ; Gene Expression Regulation ; Immunity, Innate ; Interleukin-1/metabolism ; Interleukin-17/metabolism ; Interleukin-23/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mouth Mucosa/microbiology ; Mouth Mucosa/physiology ; Receptors, Interleukin-1/genetics ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/metabolism
    Chemical Substances Adaptor Proteins, Signal Transducing ; ECE1 protein, Candida albicans ; Fungal Proteins ; Interleukin-1 ; Interleukin-17 ; Interleukin-23 ; Receptors, Interleukin-1 ; Traf3ip2 protein, mouse ; interleukin-36 receptor, mouse ; interleukin-36, mouse ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2018-06-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1800515
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ud II Zs.37: Show issues Location:
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    Zs.MG 28: Show issues

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