Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1783505141002928128 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7065885 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT boguslawskikm exploitingspeciesspecificitytounderstandthetropismofahumanspecifictoxin AT mckeownan exploitingspeciesspecificitytounderstandthetropismofahumanspecifictoxin AT daycj exploitingspeciesspecificitytounderstandthetropismofahumanspecifictoxin AT laceyka exploitingspeciesspecificitytounderstandthetropismofahumanspecifictoxin AT tamk exploitingspeciesspecificitytounderstandthetropismofahumanspecifictoxin AT vozhillan exploitingspeciesspecificitytounderstandthetropismofahumanspecifictoxin AT kimsy exploitingspeciesspecificitytounderstandthetropismofahumanspecifictoxin AT jenningsmp exploitingspeciesspecificitytounderstandthetropismofahumanspecifictoxin AT koralovsb exploitingspeciesspecificitytounderstandthetropismofahumanspecifictoxin AT eldenc exploitingspeciesspecificitytounderstandthetropismofahumanspecifictoxin AT torresvj exploitingspeciesspecificitytounderstandthetropismofahumanspecifictoxin |