Expression of δ-toxin by Staphylococcus aureus mediates escape from phago-endosomes of human epithelial and endothelial cells in the presence of β-toxin

Giese, Bernd; Glowinski, Frithjof; Paprotka, Kerstin; Dittmann, Silvia; Steiner, Tobias; Sinha, Bhanu; Fraunholz, Martin

doi:10.1111/j.1462-5822.2010.01538.x

Cited by 99 publications

(124 citation statements)

References 59 publications

(111 reference statements)

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“…This observation is consistent with a report by Kobayashi et al describing the escape of different USA300 strains from PMNs, where the investigators concluded that escape from PMNs by S. aureus was independent of toxins when evaluated 6 h postinfection (42). In light of this new role for LukAB, which may be shared with other staphylococcal factors such as delta hemolysin and beta hemolysin (48) and PSMs (38,43), vaccine strategies that aim to promote phagocyte-mediated killing of S. aureus through opsonization may prove to be ineffective. Our data show that opsonization does cause PMN-mediated killing of USA300, but factors such as LukAB allow the early escape and propagation of surviving bacteria.…”

Section: Discussionsupporting

confidence: 82%

Staphylococcus aureus Elaborates Leukocidin AB To Mediate Escape from within Human Neutrophils

et al. 2013

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bMethicillin-resistant Staphylococcus aureus (MRSA) strains of the pulsed-field type USA300 are primarily responsible for the current community-associated epidemic of MRSA infections in the United States. The success of USA300 is partly attributed to the ability of the pathogen to avoid destruction by human neutrophils (polymorphonuclear leukocytes [PMNs]), which are crucial to the host immune response to S. aureus infection. In this work, we investigated the contribution of bicomponent poreforming toxins to the ability of USA300 to withstand attack from primary human PMNs. We demonstrate that in vitro growth conditions influence the expression, production, and availability of leukotoxins by USA300, which in turn impact the cytotoxic potential of this clone toward PMNs. Interestingly, we also found that upon exposure to PMNs, USA300 preferentially activates the promoter of the lukAB operon, which encodes the recently identified leukocidin AB (LukAB). LukAB elaborated by extracellular S. aureus forms pores in the plasma membrane of PMNs, leading to PMN lysis, highlighting a contribution of LukAB to USA300 virulence. We now show that LukAB also facilitates the escape of bacteria engulfed within PMNs, in turn enabling the replication and outgrowth of S. aureus. Together, these results suggest that upon encountering PMNs S. aureus induces the production of LukAB, which serves as an extra-and intracellular weapon to protect the bacterium from destruction by human PMNs.

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Section: Discussionsupporting

confidence: 82%

Staphylococcus aureus Elaborates Leukocidin AB To Mediate Escape from within Human Neutrophils

et al. 2013

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“…Here, we show that within 1 h of macrophage infection, the majority of USA300 bacteria are sequestered within acidic phagosomes and that the bacteria remain in acidic compartments during 8 h of infection. Previous studies demonstrated escape of S. aureus strains from vacuoles of nonphagocytic cells within hours of infection (13,55,61,62). However, we demonstrate that during macrophage infection, over 90% of USA300 bacteria are enclosed within intracellular compartments as that proportion of bacteria was localized within acidic vesicles at 8 h p.i.…”

Section: Discussioncontrasting

confidence: 37%

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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“…Recent work showed that staphylococci can escape from their initial phagosomes to the cytoplasm by expressing delta-toxin and/or the PSM-alpha protein, whereas some strainspecific differences are possible (184,185). The location where bacteria form SCVs and persist for long periods might be the cytoplasm, but this is not precisely known.…”

Section: Other Factors That Induce the Formation Of Scvs During In VImentioning

confidence: 99%

Clinical Significance and Pathogenesis of Staphylococcal Small Colony Variants in Persistent Infections

2016

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SUMMARYSmall colony variants (SCVs) were first described more than 100 years ago forStaphylococcus aureusand various coagulase-negative staphylococci. Two decades ago, an association between chronic staphylococcal infections and the presence of SCVs was observed. Since then, many clinical studies and observations have been published which tie recurrent, persistent staphylococcal infections, including device-associated infections, bone and tissue infections, and airway infections of cystic fibrosis patients, to this special phenotype. By their intracellular lifestyle, SCVs exhibit so-called phenotypic (or functional) resistance beyond the classical resistance mechanisms, and they can often be retrieved from therapy-refractory courses of infection. In this review, the various clinical infections where SCVs can be expected and isolated, diagnostic procedures for optimized species confirmation, and the pathogenesis of SCVs, including defined underlying molecular mechanisms and the phenotype switch phenomenon, are presented. Moreover, relevant animal models and suggested treatment regimens, as well as the requirements for future research areas, are highlighted.

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Expression of δ-toxin by Staphylococcus aureus mediates escape from phago-endosomes of human epithelial and endothelial cells in the presence of β-toxin

Cited by 99 publications

References 59 publications

Staphylococcus aureus Elaborates Leukocidin AB To Mediate Escape from within Human Neutrophils

Staphylococcus aureus Elaborates Leukocidin AB To Mediate Escape from within Human Neutrophils

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

Clinical Significance and Pathogenesis of Staphylococcal Small Colony Variants in Persistent Infections

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