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  1. Article ; Online: Vaccination with VLPs Presenting a Linear Neutralizing Domain of S. aureus Hla Elicits Protective Immunity

    Jason A. Joyner / Seth M. Daly / Julianne Peabody / Kathleen D. Triplett / Srijana Pokhrel / Bradley O. Elmore / Diane Adebanjo / David S. Peabody / Bryce Chackerian / Pamela R. Hall

    Toxins, Vol 12, Iss 450, p

    2020  Volume 450

    Abstract: The pore-forming cytotoxin α-hemolysin, or Hla, is a critical Staphylococcus aureus virulence factor that promotes infection by causing tissue damage, excessive inflammation, and lysis of both innate and adaptive immune cells, among other cellular ... ...

    Abstract The pore-forming cytotoxin α-hemolysin, or Hla, is a critical Staphylococcus aureus virulence factor that promotes infection by causing tissue damage, excessive inflammation, and lysis of both innate and adaptive immune cells, among other cellular targets. In this study, we asked whether a virus-like particle (VLP)-based vaccine targeting Hla could attenuate S. aureus Hla-mediated pathogenesis. VLPs are versatile vaccine platforms that can be used to display target antigens in a multivalent array, typically resulting in the induction of high titer, long-lasting antibody responses. In the present study, we describe the first VLP-based vaccines that target Hla. Vaccination with either of two VLPs displaying a 21 amino-acid linear neutralizing domain (LND) of Hla protected both male and female mice from subcutaneous Hla challenge, evident by reduction in lesion size and neutrophil influx to the site of intoxication. Antibodies elicited by VLP-LND vaccination bound both the LND peptide and the native toxin, effectively neutralizing Hla and preventing toxin-mediated lysis of target cells. We anticipate these novel and promising vaccines being part of a multi-component S. aureus vaccine to reduce severity of S. aureus infection.
    Keywords Staphylococcus aureus ; α-hemolysin ; linear neutralizing domain ; virus-like particles ; vaccine ; mice ; Medicine ; R
    Subject code 570
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Aiolos represses CD4+ T cell cytotoxic programming via reciprocal regulation of TFH transcription factors and IL-2 sensitivity

    Kaitlin A. Read / Devin M. Jones / Srijana Pokhrel / Emily D. S. Hales / Aditi Varkey / Jasmine A. Tuazon / Caprice D. Eisele / Omar Abdouni / Abbey Saadey / Melissa R. Leonard / Robert T. Warren / Michael D. Powell / Jeremy M. Boss / Emily A. Hemann / Jacob S. Yount / Gang Xin / Hazem E. Ghoneim / Chan-Wang J. Lio / Aharon G. Freud /
    Patrick L. Collins / Kenneth J. Oestreich

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 18

    Abstract: The regulation and direction of CD4+ T cells into phenotypic and functional lineages is coordinated by a complex set of mechanisms. Here the authors show a role for Aiolos as a regulator of the CD4+ cytotoxic and T follicular helper lineages. ...

    Abstract The regulation and direction of CD4+ T cells into phenotypic and functional lineages is coordinated by a complex set of mechanisms. Here the authors show a role for Aiolos as a regulator of the CD4+ cytotoxic and T follicular helper lineages.
    Keywords Science ; Q
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Counteracting H3K4 methylation modulators Set1 and Jhd2 co-regulate chromatin dynamics and gene transcription

    Saravanan Ramakrishnan / Srijana Pokhrel / Sowmiya Palani / Christian Pflueger / Timothy J. Parnell / Bradley R. Cairns / Srividya Bhaskara / Mahesh B. Chandrasekharan

    Nature Communications, Vol 7, Iss 1, Pp 1-

    2016  Volume 16

    Abstract: Histone H3K4 methylation affects gene transcription from yeast to humans. Here, the authors show that Set1 and Jhd2, the only H3K4 methyltransferase and H3K4 demethylase, respectively, in budding yeast, co-regulate both positive and negative ... ...

    Abstract Histone H3K4 methylation affects gene transcription from yeast to humans. Here, the authors show that Set1 and Jhd2, the only H3K4 methyltransferase and H3K4 demethylase, respectively, in budding yeast, co-regulate both positive and negative transcription mediated by nucleosomal turnover and occupancy.
    Keywords Science ; Q
    Language English
    Publishing date 2016-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: GPER activation protects against epithelial barrier disruption by Staphylococcus aureus α-toxin

    Kathleen D. Triplett / Srijana Pokhrel / Moriah J. Castleman / Seth M. Daly / Bradley O. Elmore / Jason A. Joyner / Geetanjali Sharma / Guy Herbert / Matthew J. Campen / Helen J. Hathaway / Eric R. Prossnitz / Pamela R. Hall

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 12

    Abstract: Abstract Sex bias in innate defense against Staphylococcus aureus skin and soft tissue infection (SSTI) is dependent on both estrogen production by the host and S. aureus secretion of the virulence factor, α-hemolysin (Hla). The impact of estrogen ... ...

    Abstract Abstract Sex bias in innate defense against Staphylococcus aureus skin and soft tissue infection (SSTI) is dependent on both estrogen production by the host and S. aureus secretion of the virulence factor, α-hemolysin (Hla). The impact of estrogen signaling on the immune system is most often studied in terms of the nuclear estrogen receptors ERα and ERβ. However, the potential contribution of the G protein-coupled estrogen receptor (GPER) to innate defense against infectious disease, particularly with respect to skin infection, has not been addressed. Using a murine model of SSTI, we found that GPER activation with the highly selective agonist G-1 limits S. aureus SSTI and Hla-mediated pathogenesis, effects that were absent in GPER knockout mice. Specifically, G-1 reduced Hla-mediated skin lesion formation and pro-inflammatory cytokine production, while increasing bacterial clearance. In vitro, G-1 reduced surface expression of the Hla receptor, ADAM10, in a human keratinocyte cell line and increased resistance to Hla-mediated permeability barrier disruption. This novel role for GPER activation in skin innate defense against infectious disease suggests that G-1 may have clinical utility in patients with epithelial permeability barrier dysfunction or who are otherwise at increased risk of S. aureus infection, including those with atopic dermatitis or cancer.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2019-02-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: VLP-based vaccine induces immune control of Staphylococcus aureus virulence regulation

    Seth M. Daly / Jason A. Joyner / Kathleen D. Triplett / Bradley O. Elmore / Srijana Pokhrel / Kathryn M. Frietze / David S. Peabody / Bryce Chackerian / Pamela R. Hall

    Scientific Reports, Vol 7, Iss 1, Pp 1-

    2017  Volume 12

    Abstract: Abstract Staphylococcus aureus is the leading cause of skin and soft tissue infections (SSTIs) and mounting antibiotic resistance requires innovative treatment strategies. S. aureus uses secreted cyclic autoinducing peptides (AIPs) and the accessory gene ...

    Abstract Abstract Staphylococcus aureus is the leading cause of skin and soft tissue infections (SSTIs) and mounting antibiotic resistance requires innovative treatment strategies. S. aureus uses secreted cyclic autoinducing peptides (AIPs) and the accessory gene regulator (agr) operon to coordinate expression of virulence factors required for invasive infection. Of the four agr alleles (agr types I-IV and corresponding AIPs1-4), agr type I isolates are most frequently associated with invasive infection. Cyclization via a thiolactone bond is essential for AIP function; therefore, recognition of the cyclic form of AIP1 may be necessary for antibody-mediated neutralization. However, the small sizes of AIPs and labile thiolactone bond have hindered vaccine development. To overcome this, we used a virus-like particle (VLP) vaccine platform (PP7) for conformationally-restricted presentation of a modified AIP1 amino acid sequence (AIP1S). Vaccination with PP7-AIP1S elicited AIP1-specific antibodies and limited agr-activation in vivo. Importantly, in a murine SSTI challenge model with a highly virulent agr type I S. aureus isolate, PP7-AIP1S vaccination reduced pathogenesis and increased bacterial clearance compared to controls, demonstrating vaccine efficacy. Given the contribution of MRSA agr type I isolates to human disease, vaccine targeting of AIP1-regulated virulence could have a major clinical impact in the fight against antibiotic resistance.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2017-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    Inter-library loan at ZB MED

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