The adherens junctions control susceptibility to Staphylococcus aureus α-toxin.
- Popov LM Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305;
- Marceau CD Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305;
- Starkl PM Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;
- Lumb JH Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305;
- Shah J Department of Cell Biology, University of Geneva, 1205 Geneva, Switzerland;
- Guerrera D Department of Cell Biology, University of Geneva, 1205 Geneva, Switzerland;
- Cooper RL Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305;
- Merakou C Glaxo Smith Kline Vaccines, Società a Responsabilità Limitata, 53100 Siena, Italy;
- Bouley DM Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA 94305;
- Meng W Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China; RIKEN Center for Developmental Biology, Kobe 650-0047, Japan;
- Kiyonari H Animal Resource Development Unit and Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan;
- Takeichi M RIKEN Center for Developmental Biology, Kobe 650-0047, Japan;
- Galli SJ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;
- Bagnoli F Glaxo Smith Kline Vaccines, Società a Responsabilità Limitata, 53100 Siena, Italy;
- Citi S Department of Cell Biology, University of Geneva, 1205 Geneva, Switzerland;
- Carette JE Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305; amieva@stanford.edu carette@stanford.edu.
- Amieva MR Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305 amieva@stanford.edu carette@stanford.edu.
- 2015-10-23
Published in:
- Proceedings of the National Academy of Sciences of the United States of America. - 2015
MRSA
PLEKHA7
Staphylococcus aureus
adherens junctions
α-toxin
ADAM Proteins
ADAM10 Protein
Adherens Junctions
Amyloid Precursor Protein Secretases
Animals
Bacterial Toxins
Carrier Proteins
Cell Line
Hemolysin Proteins
Humans
Membrane Proteins
Methicillin-Resistant Staphylococcus aureus
Mice
Mice, Knockout
Staphylococcal Infections
Vasculitis
English
Staphylococcus aureus is both a transient skin colonizer and a formidable human pathogen, ranking among the leading causes of skin and soft tissue infections as well as severe pneumonia. The secreted bacterial α-toxin is essential for S. aureus virulence in these epithelial diseases. To discover host cellular factors required for α-toxin cytotoxicity, we conducted a genetic screen using mutagenized haploid human cells. Our screen identified a cytoplasmic member of the adherens junctions, plekstrin-homology domain containing protein 7 (PLEKHA7), as the second most significantly enriched gene after the known α-toxin receptor, a disintegrin and metalloprotease 10 (ADAM10). Here we report a new, unexpected role for PLEKHA7 and several components of cellular adherens junctions in controlling susceptibility to S. aureus α-toxin. We find that despite being injured by α-toxin pore formation, PLEKHA7 knockout cells recover after intoxication. By infecting PLEKHA7(-/-) mice with methicillin-resistant S. aureus USA300 LAC strain, we demonstrate that this junctional protein controls disease severity in both skin infection and lethal S. aureus pneumonia. Our results suggest that adherens junctions actively control cellular responses to a potent pore-forming bacterial toxin and identify PLEKHA7 as a potential nonessential host target to reduce S. aureus virulence during epithelial infections.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1073/pnas.1510265112
- PMID 26489655
- Persistent URL
- https://sonar.ch/global/documents/240645
Statistics
Document views: 47
File downloads:
- Full-text: 0