Journal Article

The adherens junctions control susceptibility to Staphylococcus aureus α-toxin

Jan E. Carette, Wenxiang Meng, Hiroshi Kiyonari, Caleb D. Marceau, Jennifer H. Lumb, Sandra Citi, Lauren M. Popov, Manuel R. Amieva, Fabio Bagnoli, Jimit Shah, Christina Merakou, Masatoshi Takeichi, Diego Guerrera, Rachel L. Cooper, Donna M. Bouley, Stephen J. Galli, Philipp M. Starkl

2015

Overview

Staphylococcus aureus is a major cause of invasive bacterial infection. One prominent virulence factor is α-toxin, a protein that injures the cell by forming a damaging pore across the cell membrane. We conducted a genetic screen to identify host factors that control susceptibility to α-toxin. We discovered that several components of the adherens junction complex modulate α-toxin cytotoxicity. By eliminating expression of the junctional protein plekstrin-homology domain containing protein 7 (PLEKHA7), cells gained the ability to recover from α-toxin injury and mice lacking PLEKHA7 exhibited improved healing from S. aureus skin infection and enhanced survival of pneumonia. Our data suggest that targeting nonessential host epithelial junction components can reduce S. aureus morbidity by enhancing cellular resilience to α-toxin injury. 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.

• Publisher: National Acad Sciences,National Academy of Sciences
• Subject: ADAM Proteins - genetics / ADAM Proteins - metabolism / ADAM10 Protein / Adherens Junctions - genetics / Adherens Junctions - metabolism / Amyloid Precursor Protein Secretases - genetics / Amyloid Precursor Protein Secretases - metabolism / Animals / Bacterial Toxins - genetics / Bacterial Toxins - metabolism / Biological Sciences / Carrier Proteins - genetics / Carrier Proteins - metabolism / Cell Line / Hemolysin Proteins - genetics / Hemolysin Proteins - metabolism / Humans / Membrane Proteins - genetics / Membrane Proteins - metabolism / Methicillin-Resistant Staphylococcus aureus - genetics / Methicillin-Resistant Staphylococcus aureus - metabolism / Methicillin-Resistant Staphylococcus aureus - pathogenicity / Mice / Mice, Knockout / Staphylococcal Infections - genetics / Staphylococcal Infections - metabolism / Staphylococcal Infections - pathology / Staphylococcus aureus / Vasculitis - genetics / Vasculitis - metabolism / Vasculitis - microbiology / Vasculitis - pathology