The adherens junctions control susceptibility to Staphylococcus aureus α-toxin.
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.
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305;
Lauren M
LM
Popov
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305;
Caleb D
CD
Marceau
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;
Philipp M
PM
Starkl
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305;
Jennifer H
JH
Lumb
Department of Cell Biology, University of Geneva, 1205 Geneva, Switzerland;
Jimit
J
Shah
Department of Cell Biology, University of Geneva, 1205 Geneva, Switzerland;
Diego
http://orcid.org/0000-0002-5323-4447
D
Guerrera
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305;
Rachel L
RL
Cooper
Glaxo Smith Kline Vaccines, Società a Responsabilità Limitata, 53100 Siena, Italy;
Christina
C
Merakou
Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA 94305;
Donna M
DM
Bouley
Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 100101 Beijing, China; RIKEN Center for Developmental Biology, Kobe 650-0047, Japan;
Wenxiang
W
Meng
Animal Resource Development Unit and Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan;
Hiroshi
H
Kiyonari
RIKEN Center for Developmental Biology, Kobe 650-0047, Japan;
Masatoshi
M
Takeichi
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;
Stephen J
SJ
Galli
Glaxo Smith Kline Vaccines, Società a Responsabilità Limitata, 53100 Siena, Italy;
Fabio
F
Bagnoli
Department of Cell Biology, University of Geneva, 1205 Geneva, Switzerland;
Sandra
S
Citi
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305; amieva@stanford.edu carette@stanford.edu.
Jan E
JE
Carette
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.
Manuel R
MR
Amieva
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072197:ADAM10 Protein; D022005:Adherens Junctions / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D006460:Hemolysin Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D051379:Mice; D018345:Mice, Knockout; D013203:Staphylococcal Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014657:Vasculitis / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology
D001427:Bacterial Toxins; D002352:Carrier Proteins; D006460:Hemolysin Proteins; D008565:Membrane Proteins; C533786:PLEKHA7 protein, human; C584830:PLEKHA7 protein, mouse; C021091:staphylococcal alpha-toxin; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C491234:Adam10 protein, mouse
MRSA; PLEKHA7; Staphylococcus aureus; adherens junctions; α-toxin