Recovery of human fibroblasts from attack by the pore-forming α-toxin of Staphylococcus aureus

Walev, Iwan; Palmer, Michaël; Martin, E; Jonas, Daniel E; Weller, Ulrich; Höhn-Bentz, Hanni; Husmann, Matthias; Bhakdi, Sucharit

doi:10.1006/mpat.1994.1065

Cited by 67 publications

(68 citation statements)

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“…3A). In agreement with results of previous studies (40,41), amounts of alpha-toxin were essentially equal in monomeric and heptameric forms at 2 h of incubation, although the overall amounts of membranebound alpha-toxin decreased, probably due to shedding. Control and THP-1 cells showed similar amounts of monomeric and heptameric forms of alpha-toxin, indicating that pretreatment with IFN-␣ has no effect on alpha-toxin binding or oligomerization.…”

Section: Ifns Protect Cells From Alpha-toxinsupporting

confidence: 92%

Interferons Increase Cell Resistance to Staphylococcal Alpha-Toxin

et al. 2008

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Many bacterial pathogens, including Staphylococcus aureus, use a variety of pore-forming toxins as important virulence factors. Staphylococcal alpha-toxin, a prototype ␤-barrel pore-forming toxin, triggers the release of proinflammatory mediators and induces primarily necrotic death in susceptible cells. However, whether host factors released in response to staphylococcal infections may increase cell resistance to alpha-toxin is not known. Here we show that prior exposure to interferons (IFNs) prevents alpha-toxin-induced membrane permeabilization, the depletion of ATP, and cell death. Moreover, pretreatment with IFN-␣ decreases alphatoxin-induced secretion of interleukin 1␤ (IL-1␤). IFN-␣, IFN-␤, and IFN-␥ specifically protect cells from alpha-toxin, whereas tumor necrosis factor alpha (TNF-␣), IL-6, and IL-4 have no effects. Furthermore, we show that IFN-␣-induced protection from alpha-toxin is not dependent on caspase-1 or mitogen-activated protein kinases, but requires protein synthesis and fatty acid synthase activity. Our results demonstrate that IFNs may increase cell resistance to staphylococcal alpha-toxin via the regulation of lipid metabolism and suggest that interferons play a protective role during staphylococcal infections.

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Section: Ifns Protect Cells From Alpha-toxinsupporting

confidence: 92%

Interferons Increase Cell Resistance to Staphylococcal Alpha-Toxin

et al. 2008

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“…Second, internalization of toxin is required for cellular survival. The data provide a conclusive explanation for the long-standing enigma of transient membrane perforation by a-toxin [20,21], and suggest a role of endocytosis as an innate cellular defence mechanism against small membrane pores. Third, release of toxosomes enables cells to eliminate a virtually undegradable complex comprising a bacterial virulence factor.…”

Section: Undegraded A-toxin Is Expelled From Cells In the Context Of mentioning

confidence: 69%

“…Cell death is, however, not an inevitable consequence of pore-formation. Previous studies have documented the capacity of nucleated mammalian cells to cope with a limited number of membrane lesions and recover from attack by a-toxin [20][21][22]. Although mechanical lesions and large membrane pores, inflicted by streptolysin O (SLO), appear to induce rapid calcium-dependent replacement of lesioned membrane [23,24], a-toxin pores are calcium-impermeable [25], and cannot be repaired by the wounded membrane response.…”

Section: Introductionmentioning

confidence: 99%

Elimination of a bacterial pore‐forming toxin by sequential endocytosis and exocytosis

et al. 2008

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Bacterial pore forming toxin Endocytosis Exosome Innate defence mechanism Staphylococcus aureus a b s t r a c t Staphylococcus aureus a-toxin is the archetype of bacterial pore forming toxins and a key virulence factor secreted by the majority of clinical isolates of S. aureus. Toxin monomers bind to target cells and oligomerize to form small b-barrel pores in the plasma membrane. Many nucleated cells are able to repair a limited number of lesions by unknown, calcium-independent mechanisms. Here we show that cells can internalize a-toxin, that uptake is essential for cellular survival, and that pore-complexes are not proteolytically degraded, but returned to the extracellular milieu in the context of exosome-like structures, which we term toxosomes.

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“…2G). Because intracellular ATP depletion is a hallmark of α-toxin damage and ATP repletion is associated with enhanced recovery from α-toxin injury (16,35), we quantified changes in intracellular ATP levels following intoxication. Shortly after α-toxin treatment, both WT and ΔPLEKHA7 cells quickly deplete intracellular ATP.…”

Section: Plekha7-deficient Cells Exhibit Enhanced Resilience To α-Toxmentioning

confidence: 99%

The adherens junctions control susceptibility to Staphylococcus aureus α-toxin

Popov

Marceau

Starkl

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.Staphylococcus aureus | α-toxin | adherens junctions | MRSA | PLEKHA7

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Recovery of human fibroblasts from attack by the pore-forming α-toxin of Staphylococcus aureus

Cited by 67 publications

References 0 publications

Interferons Increase Cell Resistance to Staphylococcal Alpha-Toxin

Interferons Increase Cell Resistance to Staphylococcal Alpha-Toxin

Elimination of a bacterial pore‐forming toxin by sequential endocytosis and exocytosis

The adherens junctions control susceptibility to Staphylococcus aureus α-toxin

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