title: Staphylococcal Esx proteins modulate apoptosis and release of intracellular Staphylococcus aureus during infection in epithelial cells.
abstract: The opportunistic pathogen Staphylococcus aureus is one of the major causes of health care-associated infections. S. aureus is primarily an extracellular pathogen, but it was recently reported to invade and replicate in several host cell types. The ability of S. aureus to persist within cells has been implicated in resistance to antimicrobials and recurrent infections. However, few staphylococcal proteins that mediate intracellular survival have been identified. Here we examine if EsxA and EsxB, substrates of the ESAT-6-like secretion system (Ess), are important during intracellular S. aureus infection. The Esx proteins are required for staphylococcal virulence, but their functions during infection are unclear. While isogenic S. aureus esxA and esxB mutants were not defective for epithelial cell invasion in vitro, a significant increase in early/late apoptosis was observed in esxA mutant-infected cells compared to wild-type-infected cells. Impeding secretion of EsxA by deleting C-terminal residues of the protein also resulted in a significant increase of epithelial cell apoptosis. Furthermore, cells transfected with esxA showed an increased protection from apoptotic cell death. A double mutant lacking both EsxA and EsxB also induced increased apoptosis but, remarkably, was unable to escape from cells as efficiently as the single mutants or the wild type. Thus, using in vitro models of intracellular staphylococcal infection, we demonstrate that EsxA interferes with host cell apoptotic pathways and, together with EsxB, mediates the release of S. aureus from the host cell.
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy.
authors.forename: Charalampia G
authors.initials: CG
authors.lastname: Korea
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Balsamo
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Pezzicoli
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy.
authors.forename: Christina
authors.initials: C
authors.lastname: Merakou
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Tavarini
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Bagnoli
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Serruto
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy Division of Microbiology and Infection, Warwick Medical School, University of Warwick, Coventry, United Kingdom m.unnikrishnan@warwick.ac.uk.
authors.forename: Meera
authors.initials: M
authors.lastname: Unnikrishnan
mesh_terms: D017209:Apoptosis; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000382:microbiology* / Q000502:physiology*; D017353:Gene Deletion; D054884:Host-Pathogen Interactions; D006801:Humans; D013211:Staphylococcus aureus / Q000235:genetics / Q000472:pathogenicity*; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D037521:Virulence Factors