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

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...

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Autores principales: Boguslawski, K. M., McKeown, A. N., Day, C. J., Lacey, K. A., Tam, K., Vozhilla, N., Kim, S. Y., Jennings, M. P., Koralov, S. B., Elde, N. C., Torres, V. J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065885/
https://www.ncbi.nlm.nih.gov/pubmed/32195339
http://dx.doi.org/10.1126/sciadv.aax7515
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author Boguslawski, K. M.
McKeown, A. N.
Day, C. J.
Lacey, K. A.
Tam, K.
Vozhilla, N.
Kim, S. Y.
Jennings, M. P.
Koralov, S. B.
Elde, N. C.
Torres, V. J.
author_facet Boguslawski, K. M.
McKeown, A. N.
Day, C. J.
Lacey, K. A.
Tam, K.
Vozhilla, N.
Kim, S. Y.
Jennings, M. P.
Koralov, S. B.
Elde, N. C.
Torres, V. J.
author_sort Boguslawski, K. M.
collection PubMed
description 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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spelling pubmed-70658852020-03-19 Exploiting species specificity to understand the tropism of a human-specific toxin Boguslawski, K. M. McKeown, A. N. Day, C. J. Lacey, K. A. Tam, K. Vozhilla, N. Kim, S. Y. Jennings, M. P. Koralov, S. B. Elde, N. C. Torres, V. J. Sci Adv Research Articles 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. American Association for the Advancement of Science 2020-03-11 /pmc/articles/PMC7065885/ /pubmed/32195339 http://dx.doi.org/10.1126/sciadv.aax7515 Text en Copyright © 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). http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
Boguslawski, K. M.
McKeown, A. N.
Day, C. J.
Lacey, K. A.
Tam, K.
Vozhilla, N.
Kim, S. Y.
Jennings, M. P.
Koralov, S. B.
Elde, N. C.
Torres, V. J.
Exploiting species specificity to understand the tropism of a human-specific toxin
title Exploiting species specificity to understand the tropism of a human-specific toxin
title_full Exploiting species specificity to understand the tropism of a human-specific toxin
title_fullStr Exploiting species specificity to understand the tropism of a human-specific toxin
title_full_unstemmed Exploiting species specificity to understand the tropism of a human-specific toxin
title_short Exploiting species specificity to understand the tropism of a human-specific toxin
title_sort exploiting species specificity to understand the tropism of a human-specific toxin
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065885/
https://www.ncbi.nlm.nih.gov/pubmed/32195339
http://dx.doi.org/10.1126/sciadv.aax7515
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