Staphylococcus aureus activation of caspase 1/calpain signaling mediates invasion through human keratinocytes
Open accessAbstract
The USA300 strains of Staphylococcus aureus are the major cause of skin and soft tissue infection in the United States. Invasive USA300 infection has been attributed to several virulence factors, including protein A and the α-hemolysin (Hla), which cause pathology by activating host signaling cascades. Here we show that S. aureus exploits the proinflammatory bias of human keratinocytes to activate pyroptosis, a caspase 1-dependent form of inflammatory cell death, which was required for staphylococci to penetrate across a keratinocyte barrier. Keratinocyte necrosis was mediated by calpains, Ca(2+)-dependent intracellular proteases whose endogenous inhibitor, calpastatin, is targeted by Hla-induced caspase 1. Neither Panton-Valentine leukocidin nor protein A expression was essential, but inhibition of either calpain or caspase 1 activity was sufficient to prevent staphylococcal invasion across the keratinocytes. These studies suggest that pharmacological interruption of specific keratinocyte signaling cascades as well as targeting the Hla might prevent invasive skin infection by staphylococci.
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Written from the paper’s full text.
TL;DR
USA300 *Staphylococcus aureus* exploits human keratinocyte inflammatory signaling to trigger caspase 1–dependent pyroptosis, calpastatin degradation, and calpain activation, allowing the bacteria to penetrate the keratinocyte barrier. Blocking caspase 1 or calpain prevents pyroptosis and transmigration, whereas protein A and Panton-Valentine leukocidin are not required for this process.
Key findings
- Wild-type USA300 accumulated within keratinocytes by 24 hours and induced caspase 1, caspase 3, caspase 7, and IL-1β production; the α-hemolysin (Hla) mutant induced significantly less caspase 1 (*P* < .01), and pan-caspase inhibition significantly reduced IL-1β secretion (*P* < .001).
- Wild-type USA300, but not the Hla mutant, caused apoptotic and necrotic/pyroptotic keratinocyte death and HMGB1 release; pan-caspase, caspase 1–specific, or calpain inhibition reduced apoptotic and pyroptotic cell numbers.
- In Transwell assays, approximately 90% of the wild-type inoculum was recovered from the basal compartment after 24 hours; wild-type transmigration was significantly greater than the Hla mutant (*P* < .0001), the SpA mutant invaded as well as wild-type, and the PVL mutant was less effective than wild-type but more effective than the Hla mutant.
- Calpeptin or caspase 1 inhibition significantly decreased USA300 transmigration, while caspase 3 inhibition did not; only the Hla mutant showed significantly less dextran permeability across the keratinocyte barrier.
Methods
- The study used MRSA USA300 wild-type and isogenic mutants lacking protein A (SpA−), α-hemolysin (Hla−), or Panton-Valentine leukocidin (PVL−), plus the human keratinocyte HaCaT cell line and primary human organotypic keratinocyte cultures.
- Assays included bacterial transmigration across Transwell-grown keratinocytes, confocal microscopy, dextran permeability, Ca²⁺ imaging with Fluo-3/AM, apoptosis/pyroptosis detection with YO-PRO-1/propidium iodide, immunoblotting, reverse-transcription PCR, and IL-1β/caspase activity measurements.
- Inhibitors tested included calpeptin, cytochalasin D, TAPI, GM6001, caspase 3 inhibitor I, Z-VAD-FMK, Z-WEHD-FMK, and Z-YVAD-FMK; statistical comparisons used Student *t* tests and one-way ANOVA with posttests, with significance at *P* < .05.
Limitations
- The paper states that its in vitro system was restricted to keratinocytes themselves, so it did not include recruited neutrophils or other in vivo immune components that would participate in skin infection.
- The text makes evident that the conclusions rely on cultured keratinocytes and inhibitor-based pathway interruption rather than an in vivo skin infection model; some transmigration and inhibitor results are also described as data not shown, and the PVL mutant’s intermediate phenotype is not fully resolved.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
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Claims the paper makes
0 of 10 cited sources checked · 0 supported · 0 flagged
- Findingown data
Staphylococcus aureus USA300 activates pyroptosis in human keratinocytes.
“Here we show that S. aureus exploits the proinflammatory bias of human keratinocytes to activate pyroptosis, a caspase 1-dependent form of inflammatory cell death”
- Also stated in: § USA300 Activates Apoptosis and Pyroptosis in Human Keratinocytes · plain
“After 2 hours of exposure to WT USA300 but not the Hla -mutant, both apoptotic and necrotic keratinocytes were observed (Figure 4A).”
Quote in the paperSubstantial claim- Rests on an assumption: HaCaT cells are a valid model of normal human keratinocytes.
- Also stated in: § USA300 Activates Apoptosis and Pyroptosis in Human Keratinocytes · plain
- Findingown data
The pyroptosis activated by S. aureus in keratinocytes is caspase 1-dependent.
“activate pyroptosis, a caspase 1-dependent form of inflammatory cell death”
- Also stated in: § USA300 Activates Apoptosis and Pyroptosis in Human Keratinocytes · plain
“In the presence of a pan-caspase or a caspase-1specific inhibitor, the numbers of both apoptotic and necrotic/ pyroptotic cells decreased significantly (Figure 4B).”
Quote in the paperSubstantial claim- Rests on an assumption: Z-WEHD-FMK specifically inhibits caspase 1.
- Also stated in: § USA300 Activates Apoptosis and Pyroptosis in Human Keratinocytes · plain
- Findingcitation
Human keratinocytes constitutively express pro-IL-1β.
“We postulated that constitutive expression of pro-IL-1β by keratinocytes [20] as shown (Figure 2A) would prime them for activation of the inflammasome.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Feldmeyer, 2007, The inflammasome mediates UVB-induced activation and secretion of interleukin-1beta by keratinocytes, Curr Biol source
Not checked in the free run.
- Findingown data
Protein A expression is not essential for S. aureus transmigration across keratinocytes.
“the SpA -strain invaded as well as the WT control”
Quote in the paperNot a substantial claim- Rests on an assumption: The Hla, PVL, and SpA mutant strains are isogenic with WT except for the deleted gene.
- Findingown data
Protein A expression is not essential for S. aureus activation of apoptosis or necrosis in keratinocytes.
“PVL -and SpA -mutants activated apoptosis and necrosis at rates similar to the WT strain”
Quote in the paperNot a substantial claim- Rests on an assumption: The Hla, PVL, and SpA mutant strains are isogenic with WT except for the deleted gene.
- Findingown data
USA300 exposure causes thickening and vacuolization in organotypic human keratinocyte cultures after 24 hours.
“Following a 24-hour incubation with USA300 S. aureus, human keratinocytes in primary culture remained intact; the basal layers of keratinocytes showed vacuolization and the proliferating layers were obviously thickened”
Quote in the paperNot a substantial claim - Findingown data
Hla mutant is associated with significantly less dextran permeability across keratinocyte barrier.
“Only the Hla -strain was associated with significantly less dextran permeability”
Quote in the paperSubstantial claim- Rests on an assumption: Transmigration of S. aureus across HaCaT monolayers on Transwells models penetration through the human keratinocyte barrier in skin.
- Rests on an assumption: The Hla- mutant lacks only Hla and its phenotype is due to absence of Hla.
- Findingown data
WT USA300 transmigration across HaCaT monolayers is significantly greater than Hla mutant.
“There was significantly greater transmigration of the WT USA300 strain than the Hla -mutant (P < .0001)”
Quote in the paperSubstantial claim- Rests on an assumption: Transmigration of S. aureus across HaCaT monolayers on Transwells models penetration through the human keratinocyte barrier in skin.
- Rests on an assumption: The Hla- mutant lacks only Hla and its phenotype is due to absence of Hla.
- Findingown data
Pretreatment with calpeptin or caspase 1 inhibitor, but not caspase 3 inhibitor, significantly decreases the fraction of necrotic/pyroptotic keratinocytes.
“Pretreatment of the keratinocytes with either calpeptin or a caspase 1 inhibitor, but not a caspase 3 inhibitor, significantly decreased this fraction of necrotic, and in this case specifically pyroptotic, cells (Figure 5B).”
Quote in the paperSubstantial claim- Rests on an assumption: Calpeptin specifically inhibits calpains without affecting other pathways relevant to pyroptosis or transmigration.
- Rests on an assumption: Z-WEHD-FMK specifically inhibits caspase 1.
- Findingown data
Calpastatin, the endogenous calpain inhibitor, is targeted by Hla-induced caspase 1.
“whose endogenous inhibitor, calpastatin, is targeted by Hla-induced caspase 1”
- Also stated in: § USA300 Activation of Keratinocyte Calpain Activity · boosted
“This was confirmed in immunoblots showing calpastatin breakdown in keratinocytes stimulated with WT S. aureus that are capable of activating caspase 1, but not in response to the Hla -mutant”
Quote in the paperSubstantial claim- Rests on an assumption: The Hla- mutant lacks only Hla and its phenotype is due to absence of Hla.
- Also stated in: § USA300 Activation of Keratinocyte Calpain Activity · boosted
- Findingown data
S. aureus strains induce significant IL-1β production in keratinocytes.
“In response to these S. aureus strains, there was significant production of IL-1β”
Quote in the paperSubstantial claim - Findingown data
PVL expression is not essential for S. aureus activation of apoptosis or necrosis in keratinocytes.
“PVL -and SpA -mutants activated apoptosis and necrosis at rates similar to the WT strain”
Quote in the paperSubstantial claim- Rests on an assumption: The Hla, PVL, and SpA mutant strains are isogenic with WT except for the deleted gene.
- Findingcitation
USA300 induces Ca2+ flux in HaCaT cells required for calpain activity.
“as well as the generation of Ca 2+ flux (Figure 3B) required for calpain activity in response to USA300 [22].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Chun, 2009, TLR2-induced calpain cleavage of epithelial junctional proteins facilitates leukocyte transmigration, Cell Host Microbe source
Not checked in the free run.
- Rests on an assumption: HaCaT cells are a valid model of normal human keratinocytes.
- Findingown data
Inhibition of calpain or caspase 1 activity prevents staphylococcal invasion across keratinocytes.
“inhibition of either calpain or caspase 1 activity was sufficient to prevent staphylococcal invasion across the keratinocytes”
- Also stated in: § Caspase 1 or Calpain Inhibitors Prevent USA300 Penetration Through Keratinocytes · plain
“USA300 transmigration across HaCaTs treated with calpeptin, a calpain inhibitor, or a caspase 1 inhibitor was significantly decreased whereas treatment of the keratinocytes with a caspase 3 inhibitor did not alter rates of transmigration”
Quote in the paperSubstantial claim- Rests on an assumption: Transmigration of S. aureus across HaCaT monolayers on Transwells models penetration through the human keratinocyte barrier in skin.
- Rests on an assumption: Calpeptin specifically inhibits calpains without affecting other pathways relevant to pyroptosis or transmigration.
- Rests on an assumption: Z-WEHD-FMK specifically inhibits caspase 1.
- Also stated in: § Caspase 1 or Calpain Inhibitors Prevent USA300 Penetration Through Keratinocytes · plain
- Findingown data
Calpeptin treatment significantly decreases apoptotic and necrotic/pyroptotic keratinocytes.
“Treatment of the keratinocytes with calpeptin significantly decreased the numbers of both apoptotic and necrotic/ pyroptotic cells”
Quote in the paperSubstantial claim- Rests on an assumption: Calpeptin specifically inhibits calpains without affecting other pathways relevant to pyroptosis or transmigration.
- Interpretationown data
Caspase 1-dependent pyroptosis is required for staphylococci to penetrate across a keratinocyte barrier.
“which was required for staphylococci to penetrate across a keratinocyte barrier”
- Also stated in: § Caspase 1 or Calpain Inhibitors Prevent USA300 Penetration Through Keratinocytes · plain
“USA300 transmigration across HaCaTs treated with calpeptin, a calpain inhibitor, or a caspase 1 inhibitor was significantly decreased”
Quote in the paperSubstantial claim- Rests on an assumption: Transmigration of S. aureus across HaCaT monolayers on Transwells models penetration through the human keratinocyte barrier in skin.
- Also stated in: § Caspase 1 or Calpain Inhibitors Prevent USA300 Penetration Through Keratinocytes · plain
- Interpretationown data
The majority of IL-1β production in this setting is from inflammasome activation.
“that was significantly decreased in cells treated with a pan-caspase inhibitor (Figure 2D), indicating that the majority of IL-1β production in this setting is from inflammasome activation.”
Quote in the paperSubstantial claim - Interpretationreasoning
Focal accumulation of PMNs as a consequence of inflammasome activation in skin results in pustule or abscess formation characteristic of S. aureus skin infection.
“As a consequence of inflammasome activation in the skin, focal accumulation of PMNs results in the pustule or abscess formation characteristic of S. aureus skin infection.”
Quote in the paperSubstantial claim - Interpretationreasoning
The ability of keratinocytes to proliferate in response to S. aureus likely prevents invasive infection.
“The ability of keratinocytes to proliferate in response to S. aureus is also likely to prevent invasive infection.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The interaction of Hla with ADAM-10 may also contribute to penetration through skin, accounting for transmigration not inhibited by calpain or caspase 1 inhibitors.
“This interaction may also contribute to penetration through the skin, accounting for the transmigration that is not inhibited in the presence of calpain or caspase 1 inhibitors.”
Quote in the paperNot a substantial claim - Premisecitation
Hla production is critical for skin infection.
“Participation of the α-hemolysin (Hla) in the pathogenesis of skin infection is well documented [4][5][6]”
- Also stated in: § DISCUSSION · boosted
“Hla production is clearly critical for skin infection”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4][5][6]
Not checked in the free run.
- Also stated in: § DISCUSSION · boosted
- Interpretationreasoning
Human keratinocytes, even without recruited phagocytes, are remarkably resistant to S. aureus penetration.
“Human keratinocytes, even in the absence of recruited phagocytes, are remarkably resistant to S. aureus penetration.”
Quote in the paperSubstantial claim- Rests on an assumption: HaCaT cells are a valid model of normal human keratinocytes.
- Interpretationown data
Keratinocyte necrosis is mediated by calpains.
“Keratinocyte necrosis was mediated by calpains”
- Also stated in: § Calpain or Caspase 1 Inhibitors Rescue Keratinocytes From Hla-Mediated Pyroptosis · plain
“Treatment of the keratinocytes with calpeptin significantly decreased the numbers of both apoptotic and necrotic/ pyroptotic cells”
Quote in the paperSubstantial claim- Rests on an assumption: Calpeptin specifically inhibits calpains without affecting other pathways relevant to pyroptosis or transmigration.
- Also stated in: § Calpain or Caspase 1 Inhibitors Rescue Keratinocytes From Hla-Mediated Pyroptosis · plain
- Premisecitation
Protein A is essential for staphylococci to penetrate across an airway epithelial barrier.
“whereas protein A, which was entirely dispensable in the activation of pyroptosis of keratinocytes, was essential to enable staphylococci to penetrate across an airway epithelial barrier [13].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Soong, 2011, Staphylococcus aureus protein A mediates invasion across airway epithelial cells through activation of RhoA GTPase signaling and proteolytic activity, J Biol Chem source
Not checked in the free run.
- Interpretationown data
Induction of keratinocyte signaling and specifically calpain activity is critical for staphylococcal invasion.
“The induction of keratinocyte signaling and specifically calpain activity was critical for staphylococcal invasion.”
Quote in the paperSubstantial claim - Premisecitation
Hla contributes to barrier dysfunction in A549 cells through interaction with ADAM-10 and cleavage of E-cadherin.
“Hla also contributes to barrier dysfunction in A549 cells through its interaction with ADAM-10 and cleavage of E-cadherin [27].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27] Inoshima, 2011, A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice, Nat Med source
Not checked in the free run.
- May combine two claims. 20
- Classified as probably not a substantial claim. 2
May combine two claims.
Findingown dataPVL expression contributes to transmigration across keratinocytes, though less than Hla.
“The PVL -strain was also less capable of transmigration but not as deficient as the Hla - strain.”
- Also stated in: § DISCUSSION · plain
“The PVL -strain was less effective in transmigration across the keratinocytes, but the same mutant was as effective as the parental strain in stimulating pyroptosis.”
Quote in the paperSubstantial claim- Rests on an assumption: The Hla, PVL, and SpA mutant strains are isogenic with WT except for the deleted gene.
- Also stated in: § DISCUSSION · plain
May combine two claims.
Findingown dataHaCaT cells express calpains 1 and 2 and calpastatin.
“we first confirmed the expression of calpains 1 and 2 and calpastatin in the HaCaT cells (Figure 3A)”
Quote in the paperSubstantial claim- Rests on an assumption: HaCaT cells are a valid model of normal human keratinocytes.
May combine two claims.
Findingown dataAt 4 hours, USA300 is on the surface of polarized HaCaT cells with no evidence of internalization or paracellular invasion.
“Confocal images demonstrated USA300 on the surface of polarized HaCaT cells, a human keratinocyte cell line, at 4 hours but no evidence of internalization or paracellular invasion at that time”
Quote in the paperNot a substantial claim- Rests on an assumption: HaCaT cells are a valid model of normal human keratinocytes.
May combine two claims.
Findingown dataWT USA300 but not Hla mutant generates a population of smaller, condensed keratinocytes.
“a population of smaller, condensed keratinocytes was readily apparent in the HaCaTs exposed to WT but not Hla -staphylococci (Figure 5A).”
Quote in the paperSubstantial claim- Rests on an assumption: The Hla- mutant lacks only Hla and its phenotype is due to absence of Hla.
May combine two claims.
Findingown dataPan-caspase or caspase-1 specific inhibition significantly decreases both apoptotic and necrotic/pyroptotic keratinocytes.
“In the presence of a pan-caspase or a caspase-1specific inhibitor, the numbers of both apoptotic and necrotic/ pyroptotic cells decreased significantly (Figure 4B).”
Quote in the paperSubstantial claim- Rests on an assumption: Z-WEHD-FMK specifically inhibits caspase 1.
May combine two claims.
Findingown dataWT USA300 but not Hla mutant induces HMGB1 release from keratinocytes, indicating necrosis.
“Release of HMGB1 from the cells exposed to WT USA300 but not the Hla -mutant further indicated the induction of necrosis and activation of another proinflammatory signal (Figure 4C).”
Quote in the paperSubstantial claim- Rests on an assumption: The Hla- mutant lacks only Hla and its phenotype is due to absence of Hla.
May combine two claims.
Findingown dataCytochalasin D, TAPI, and GM6001 do not inhibit S. aureus transmigration across keratinocytes.
“Cytochalasin D treatment of the HaCaTs, which prevents the endocytosis of S. aureus or its components [25], the metalloproteinase inhibitor TAPI, and a general protease inhibitor, GM6001, did not inhibit transmigration (data not shown).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Edwards, 2011, Staphylococcus aureus keratinocyte invasion is dependent upon multiple high-affinity fibronectin-binding repeats within FnBPA, PLoS One source
Not checked in the free run.
May combine two claims.
Findingown dataUSA300 accumulates within keratinocytes at 24 hours, primarily at the apical surface, and is not observed in paracellular spaces.
“At 24 hours staphylococci appeared to have accumulated within keratinocytes, in a focal distribution pattern, primarily at the apical surface of the cell cultures”
- Also stated in: § USA300 Accumulates Within Keratinocytes · plain
“Staphylococci were not observed within the paracellular spaces.”
Quote in the paperSubstantial claim- Rests on an assumption: HaCaT cells are a valid model of normal human keratinocytes.
- Also stated in: § USA300 Accumulates Within Keratinocytes · plain
May combine two claims.
Findingown dataWT USA300, but not Hla mutant, activates calpastatin degradation in keratinocytes through caspase 1 activation.
“This was confirmed in immunoblots showing calpastatin breakdown in keratinocytes stimulated with WT S. aureus that are capable of activating caspase 1, but not in response to the Hla -mutant or in cells pretreated with calpeptin”
Quote in the paperSubstantial claim- Rests on an assumption: The Hla- mutant lacks only Hla and its phenotype is due to absence of Hla.
- Rests on an assumption: Calpeptin specifically inhibits calpains without affecting other pathways relevant to pyroptosis or transmigration.
May combine two claims.
Findingown dataAfter 2 hours, WT USA300 but not Hla mutant induces both apoptotic and necrotic keratinocytes.
“After 2 hours of exposure to WT USA300 but not the Hla -mutant, both apoptotic and necrotic keratinocytes were observed (Figure 4A).”
Quote in the paperSubstantial claim- Rests on an assumption: The Hla- mutant lacks only Hla and its phenotype is due to absence of Hla.
May combine two claims.
InterpretationcitationHla stimulates epithelial proliferation via EGFR, so keratinocyte infection results in focal areas of infection and induction of more keratinocytes rather than widespread loss of barrier function.
“As S. aureus Hla stimulates epithelial proliferation via EGFR [15], keratinocyte infection does not result in widespread loss of barrier function but instead results in focal areas of infection and induction of more keratinocytes to replace the necrotic cells.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Haugwitz, 2006, Pore-forming Staphylococcus aureus alpha-toxin triggers epidermal growth factor receptor-dependent proliferation, Cell Microbiol source
Not checked in the free run.
May combine two claims.
Interpretationown dataHla, but not PVL, is critical for disruption of keratinocyte barrier integrity.
“suggesting that Hla but not PVL was critical in the disruption of the integrity of the keratinocyte barrier.”
Quote in the paperSubstantial claim- Rests on an assumption: Transmigration of S. aureus across HaCaT monolayers on Transwells models penetration through the human keratinocyte barrier in skin.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningPVL pore formation may act in concert with Hla to enhance keratinocyte pyroptosis but is not a critical factor.
“It is possible that PVL pore formation acts in concert with Hla to enhance keratinocyte pyroptosis but is not a critical factor.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationCalpains participate in PMN recruitment across airway epithelial barriers, with Ca2+ flux induced through TLR2 signaling as the stimulus.
“We have previously found that calpains participate in PMN recruitment across airway epithelial barriers [22].In those studies, the stimulus for calpain activity was the Ca 2+ flux induced through TLR2 signaling”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Chun, 2009, TLR2-induced calpain cleavage of epithelial junctional proteins facilitates leukocyte transmigration, Cell Host Microbe source
Not checked in the free run.
May combine two claims.
Interpretationown dataWhile keratinocytes undergo degradation, S. aureus appears to proliferate intracellularly, having activated keratinocyte destruction and evaded toxicity.
“While the keratinocytes are undergoing degradation, the organisms appear to proliferate intracellularly, having activated the destruction of the keratinocyte and evaded the toxicity of the keratinocyte products.”
Quote in the paperSubstantial claim- Rests on an assumption: HaCaT cells are a valid model of normal human keratinocytes.
May combine two claims.
InterpretationcitationKeratinocytes are primed for inflammasome activation by surface contact with staphylococci because they constitutively express IL-1β, unlike macrophages which require internalization of peptidoglycan.
“In contrast to macrophages, which require the internalization of particulate peptidoglycan to activate inflammasome signaling [17], keratinocytes constitutively express IL-1β and thus are primed for activation by surface contact with staphylococci.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Shimada, 2010, Staphylococcus aureus evades lysozyme-based peptidoglycan digestion that links phagocytosis, inflammasome activation, and IL-1beta secretion, Cell Host Microbe source
Not checked in the free run.
May combine two claims.
InterpretationcitationIn vivo, PMNs would be recruited and activated through inflammasome-mediated signaling by IL-1β and calpain-mediated cleavage of paracellular junctional proteins.
“in vivo, PMNs would be recruited and activated through inflammasome-mediated signaling: by IL-1β and by calpain-mediated cleavage of paracellular junctional proteins to facilitate their recruitment [22].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Chun, 2009, TLR2-induced calpain cleavage of epithelial junctional proteins facilitates leukocyte transmigration, Cell Host Microbe source
Not checked in the free run.
May combine two claims.
Interpretationown dataInhibition of caspase 1 or calpain activity protects keratinocytes from pyroptosis and staphylococcal penetration.
“Thus, inhibition of caspase 1 or calpain activity protected the keratinocytes from pyroptosis and staphylococcal penetration.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable). May combine two claims.
InterpretationreasoningRecognition that the caspase 1/calpain cascade in keratinocytes is a major cause of S. aureus-induced pathology could provide new targets for topical antistaphylococcal therapy and drugs inhibiting Hla.
“Recognition that the caspase 1/calpain cascade in keratinocytes is a major cause of the pathology induced by S. aureus could provide new targets for topical antistaphylococcal therapy, as well as provide new impetus for drugs that inhibit S. aureus Hla activity.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe proinflammatory bias of human keratinocytes and expression of specific staphylococcal toxins, particularly Hla, result in focal skin infection.
“Our data suggest that it is the proinflammatory bias of human keratinocytes and the expression of specific staphylococcal toxins, particularly Hla, that result in focal skin infection.”
Quote in the paperSubstantial claim- Rests on an assumption: HaCaT cells are a valid model of normal human keratinocytes.
- Rests on an assumption: Transmigration of S. aureus across HaCaT monolayers on Transwells models penetration through the human keratinocyte barrier in skin.
The paper relies on this without support.
HaCaT cells are a valid model of normal human keratinocytes.
“The human keratinocyte HaCaT cell line was obtained from Angela Christiano (Columbia University)”
“Confocal images demonstrated USA300 on the surface of polarized HaCaT cells, a human keratinocyte cell line”
The paper relies on this without support.
Transmigration of S. aureus across HaCaT monolayers on Transwells models penetration through the human keratinocyte barrier in skin.
“This hypothesis was tested by comparing the numbers of WT versus Hla -mutants able to penetrate through HaCaTs grown on Transwells (Corning-Costar) (Figure 6A).”
“USA300 transmigration across HaCaTs treated with calpeptin, a calpain inhibitor, or a caspase 1 inhibitor was significantly decreased”
The paper relies on this without support.
The Hla- mutant lacks only Hla and its phenotype is due to absence of Hla.
“USA300 WT and Hla -mutant were provided by Juliane Bubeck-Wardenburg (University of Chicago)”
“After 2 hours of exposure to WT USA300 but not the Hla -mutant, both apoptotic and necrotic keratinocytes were observed”
The paper relies on this without support.
Calpeptin specifically inhibits calpains without affecting other pathways relevant to pyroptosis or transmigration.
“calpeptin (20 μM)”
“calpeptin, a calpain inhibitor expected to interfere with caspase binding”
The paper relies on this without support.
Z-WEHD-FMK specifically inhibits caspase 1.
“the specific caspase 1 inhibitor Z-WEHD-FMK were added at the same time as bacteria.”
The paper relies on this without support.
YO-PRO-1/PI labeling distinguishes apoptotic from pyroptotic/necrotic keratinocytes.
“using differential fluorescent labeling (Vybrant apoptosis assay kit, YO-PRO-1/propidium iodide, Molecular Probes).”
The paper relies on this without support.
The Hla, PVL, and SpA mutant strains are isogenic with WT except for the deleted gene.
“USA300 WT and Hla -mutant were provided by Juliane Bubeck-Wardenburg (University of Chicago), and USA300 WT and Panton-Valentine leukocidin (PVL -) mutant were provided by Frank DeLeo”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
hla is important for invasion through human keratinocytes.
“Our results demonstrating induction of hla in vivo versus in vitro, regardless of P. aeruginosa presence support a recent in vitro study that showed the importance of hla for invasion through human keratinocytes [72].”
From Interactions of Methicillin Resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in Polymicrobial Wound Infection (2013) · cites this paper as [72]
pvl and spa were not important for USA300 penetration through intact epidermis.
“The same study indicated that pvl and spa were not important for USA300 penetration through intact epidermis [72], however this data cannot be fully extrapolated to the wound healing process where the epidermal barrier is compromised,”
From Interactions of Methicillin Resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in Polymicrobial Wound Infection (2013) · cites this paper as [72]
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The Inflammasome Mediates UVB-Induced Activation and Secretion of Interleukin-1β by Keratinocytes
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Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1
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- Authors
- Soong, G., Chun, J., Parker, D., & Prince, A.
- Affiliations
- Columbia University (US)
- Corresponding author
- Soong, Grace
- Venue
- The Journal of Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-03-28
- Volume
- 205
- Issue
- 10
- Pages
- 1571-1579
- ISSN
- 0022-1899 (ISSN-L)
- 1537-6613
- PMC
- PMC3415815
- OpenAlex
- W2141383182
- Semantic Scholar
- a49a2f0f96f8e2b184f776605d7ee7593a652c61
- Cited by
- 84
- References
- 27
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 8 · 2020: 4 · 2019: 7 · 2018: 3 · 2017: 8 · 2016: 9 · 2015: 7 · 2014: 7 · 2013: 8 · 2012: 5
- FWCI
- 5.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Infectious Diseases (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL079395, R01 HL79395)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P 30 AR 44535, P30AR044535)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Streptococcal Infections and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- Staphylococcus aureus, USA300, pyroptosis, caspase-1, calpain, calpastatin, alpha-hemolysin, keratinocytes, skin and soft tissue infections, bacterial invasion, Panton-Valentine leukocidin, protein A, inflammatory cell death, virulence factors
- MeSH terms
- Calcium-Binding Proteins, Calpain, Dipeptides, Enzyme Activation, Humans, Mutation, Staphylococcal Infections, Staphylococcal Skin Infections, Signal Transduction, Keratinocytes, Cysteine Proteinase Inhibitors, Apoptosis, Soft Tissue Infections, Caspase 1, Virulence Factors, Methicillin-Resistant Staphylococcus aureus, Caspase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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