Staphylococcal Esx Proteins Modulate Apoptosis and Release of Intracellular Staphylococcus aureus during Infection in Epithelial Cells

Author:

Korea Charalampia G.,Balsamo Giuliana,Pezzicoli Alfredo,Merakou Christina,Tavarini Simona,Bagnoli Fabio,Serruto Davide,Unnikrishnan Meera

Abstract

ABSTRACTThe opportunistic pathogenStaphylococcus aureusis one of the major causes of health care-associated infections.S. aureusis primarily an extracellular pathogen, but it was recently reported to invade and replicate in several host cell types. The ability ofS. aureusto 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 intracellularS. aureusinfection. The Esx proteins are required for staphylococcal virulence, but their functions during infection are unclear. While isogenicS. aureus esxAandesxBmutants were not defective for epithelial cell invasionin vitro, a significant increase in early/late apoptosis was observed inesxAmutant-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 withesxAshowed 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, usingin vitromodels of intracellular staphylococcal infection, we demonstrate that EsxA interferes with host cell apoptotic pathways and, together with EsxB, mediates the release ofS. aureusfrom the host cell.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Immunology,Microbiology,Parasitology

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