Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 46, Pages 14337-14342Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1510265112
Keywords
Staphylococcus aureus; alpha-toxin; adherens junctions; MRSA; PLEKHA7
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Funding
- Child Health Research Institute at Stanford University
- National Institute of Allergy and Infectious Diseases NIH [F31AI118212]
- National Science Foundation (NSF)
- NIH [DP2 AI104557]
- Max Kade Foundation Fellowship
- Austrian Academy of Sciences
- Austrian Science Fund [J3399-B21]
- Swiss Cancer League [KFS-2813-08-2011]
- NSF [31003A_135730/1]
- Swiss National Science Foundation (SNF) [31003A_135730] Funding Source: Swiss National Science Foundation (SNF)
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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 alpha-toxin is essential for S. aureus virulence in these epithelial diseases. To discover host cellular factors required for alpha-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 alpha-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 alpha-toxin. We find that despite being injured by alpha-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.
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