Opposing roles of σB and σB-controlled SpoVG in the global regulation of esxA in Staphylococcus aureus

Schulthess, Bettina; Bloes, Dominik Alexander; Berger‐Bächi, Brigitte

doi:10.1186/1471-2180-12-17

Cited by 44 publications

(33 citation statements)

References 50 publications

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“…EsxA is expressed as a single transcript and regulated by sigma factor B and sigma factor B-controlled SpoVG, while we do not know how EsxB is regulated (46). Secretion of EsxA and EsxB into the culture medium during growth in vitro was demonstrated previously, with mutation of EsxB affecting secretion of EsxA, and vice versa (15).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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bThe 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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…The other strains of S. aureus used in this study also possess a functional agr (75,76) (7,8). The examination of potential differences between S. aureus strains in agr expression in response to host cell conditions is important for understanding the unique features of USA300 pathogenesis and will be a focus of future studies in our lab.…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus Strain USA300 Perturbs Acquisition of Lysosomal Enzymes and Requires Phagosomal Acidification for Survival inside Macrophages

et al. 2016

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Methicillin-resistant Staphylococcus aureus (MRSA) causes invasive, drug-resistant skin and soft tissue infections. Reports that S. aureus bacteria survive inside macrophages suggest that the intramacrophage environment may be a niche for persistent infection; however, mechanisms by which the bacteria might evade macrophage phagosomal defenses are unclear. We examined the fate of the S. aureus-containing phagosome in THP-1 macrophages by evaluating bacterial intracellular survival and phagosomal acidification and maturation and by testing the impact of phagosomal conditions on bacterial viability. Multiple strains of S. aureus survived inside macrophages, and in studies using the MRSA USA300 clone, the USA300-containing phagosome acidified rapidly and acquired the late endosome and lysosome protein LAMP1. However, fewer phagosomes containing live USA300 bacteria than those containing dead bacteria associated with the lysosomal hydrolases cathepsin D and ␤-glucuronidase. Inhibiting lysosomal hydrolase activity had no impact on intracellular survival of USA300 or other S. aureus strains, suggesting that S. aureus perturbs acquisition of lysosomal enzymes. We examined the impact of acidification on S. aureus intramacrophage viability and found that inhibitors of phagosomal acidification significantly impaired USA300 intracellular survival. Inhibition of macrophage phagosomal acidification resulted in a 30-fold reduction in USA300 expression of the staphylococcal virulence regulator agr but had little effect on expression of sarA, saeR, or sigB. Bacterial exposure to acidic pH in vitro increased agr expression. Together, these results suggest that S. aureus survives inside macrophages by perturbing normal phagolysosome formation and that USA300 may sense phagosomal conditions and upregulate expression of a key virulence regulator that enables its intracellular survival. Staphylococcus aureus is the primary cause of skin and soft tissue infections (SSTIs) in humans. In the United States alone, approximately 14 million people seek medical treatment each year for SSTIs associated with methicillin-sensitive or methicillin-resistant S. aureus (MSSA or MRSA, respectively) (1), and over 50% of cases are caused by MRSA strains (2). MRSA infections can persist and disseminate to deeper sites in the host, causing diseases such as endocarditis, osteomyelitis, or bacteremia, and are estimated to cause over 18,000 deaths per year in the United States (3). High hospitalization and mortality rates associated with MRSA are attributed to the bacterium's increasing drug resistance; MRSA strains are resistant to the beta-lactam drugs penicillin, methicillin, and oxacillin, and the emergence of vancomycin-resistant strains (4) means that few treatment options remain.S. aureus was once recognized primarily as a hospital-acquired (HA) pathogen that gained access to the host via indwelling medical devices. However, strains of community-acquired MRSA (CA-MRSA) have emerged that infect healthy individuals with no predisposing risk factors f...

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“…Transcription of esxA, the first gene of the cluster, is under control of the 23 alternative sigma factor  B [54]. EsxA is required for bacterial virulence and 24 was recently shown to suppress host cell apoptosis during intracellular 25 infection [39,41,43].…”

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confidence: 99%

The Enigmatic Esx Proteins: Looking Beyond Mycobacteria

Unnikrishnan

Constantinidou

Palmer

et al. 2017

Trends in Microbiology

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1Bacteria export proteins across membranes using a range of transport 2 machineries. Type VII secretion systems (T7SSs), originally described in 3 mycobacteria, are now known to be widespread across diverse bacterial 4 phyla. Recent studies have characterized secretion components and 5 mechanisms of type VII secretion in pathogenic and environmental bacteria. A 6 variety of functions have been attributed to T7SS substrates, including 7interactions with eukaryotes and with other bacteria. Here, we evaluate the 8 growing body of knowledge on T7SSs, with focus on the non-mycobacterial 9 systems, reviewing their phylogenetic distribution, structure and function in 10 diverse settings. 11 12 3

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Opposing roles of σB and σB-controlled SpoVG in the global regulation of esxA in Staphylococcus aureus

Cited by 44 publications

References 50 publications

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

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

Staphylococcus aureus Strain USA300 Perturbs Acquisition of Lysosomal Enzymes and Requires Phagosomal Acidification for Survival inside Macrophages

The Enigmatic Esx Proteins: Looking Beyond Mycobacteria

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