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  • Exploiting species specificity to understand the tropism of a human-specific toxin

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    Version of Record (VoR)
    Author(s)
    Boguslawski, KM
    McKeow, AN
    Day, CJ
    Lacey, KA
    Tam, K
    Vozhilla, N
    Kim, SY
    Jennings, MP
    Koralov, SB
    Elde, NC
    Torres, VJ
    Griffith University Author(s)
    Jennings, Michael P.
    Day, Christopher J.
    Year published
    2020
    Metadata
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    Abstract
    American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). Many pathogens produce virulence factors that are specific toward their natural host. Clinically relevant methicillin-resistant Staphylococcus aureus (MRSA) isolates are highly adapted to humans and produce an array of human-specific virulence factors. One such factor is LukAB, a recently identified pore-forming toxin that targets human phagocytes by binding to the integrin component CD11b. LukAB exhibits strong tropism toward human, but not ...
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    American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). Many pathogens produce virulence factors that are specific toward their natural host. Clinically relevant methicillin-resistant Staphylococcus aureus (MRSA) isolates are highly adapted to humans and produce an array of human-specific virulence factors. One such factor is LukAB, a recently identified pore-forming toxin that targets human phagocytes by binding to the integrin component CD11b. LukAB exhibits strong tropism toward human, but not murine, CD11b. Here, phylogenetics and biochemical studies lead to the identification of an 11-residue domain required for the specificity of LukAB toward human CD11b, which is sufficient to render murine CD11b compatible with toxin binding. CRISPR-mediated gene editing was used to replace this domain, resulting in a “humanized” mouse. In vivo studies revealed that the humanized mice exhibit enhanced susceptibility to MRSA bloodstream infection, a phenotype mediated by LukAB. Thus, these studies establish LukAB as an important toxin for MRSA bacteremia and describe a new mouse model to study MRSA pathobiology.
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    Journal Title
    Science Advances
    Volume
    6
    Issue
    11
    DOI
    https://doi.org/10.1126/sciadv.aax7515
    Copyright Statement
    © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S.Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
    Subject
    Biological sciences
    Science & Technology
    Multidisciplinary Sciences
    Science & Technology - Other Topics
    RESISTANT STAPHYLOCOCCUS-AUREUS
    HUMAN NEUTROPHILS
    Publication URI
    http://hdl.handle.net/10072/395509
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    • Journal articles

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