Staphylococcus aureus α-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells

Robin R. Craven, Xi Gao, Irving C. Allen, Denis Gris, Juliane Bubeck Wardenburg, Erin McElvania-TeKippe, Jenny P. Ting, Joseph A. Duncan

Research output: Contribution to journalArticle

223 Citations (Scopus)

Abstract

Community Acquired Methicillin Resistant Staphylococcus aureus (CA-MRSA) causes severe necrotizing infections of the skin, soft tissues, and lungs. Staphylococcal α-hemolysin is an essential virulence factor in mouse models of CA-MRSA necrotizing pneumonia. S. aureus α-hemolysin has long been known to induce inflammatory signaling and cell death in host organisms, however the mechanism underlying these signaling events were not well understood. Using highly purified recombinant α-hemolysin, we now demonstrate that α-hemolysin activates the Nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 protein (NLRP3)-inflammasome, a host inflammatory signaling complex involved in responses to pathogens and endogenous danger signals. Non-cytolytic mutant α-hemolysin molecules fail to elicit NLRP3-inflammasome signaling, demonstrating that the responses are not due to non-specific activation of this innate immune signaling system by bacterially derived proteins. In monocyte-derived cells from humans and mice, inflammasome assembly in response to α-hemolysin results in activation of the cysteine proteinase, caspase-1. We also show that inflammasome activation by α-hemolysin works in conjunction with signaling by other CA-MRSA-derived Pathogen Associated Molecular Patterns (PAMPs) to induce secretion of pro-inflammatory cytokines IL-1β and IL-18. Additionally, α-hemolysin induces cell death in these cells through an NLRP3-dependent program of cellular necrosis, resulting in the release of endogenous pro-inflammatory molecules, like the chromatin-associated protein, High-mobility group box 1 (HMGB1). These studies link the activity of a major S. aureus virulence factor to a specific host signaling pathway. The cellular events linked to inflammasome activity have clear relevance to the disease processes associated with CA-MRSA including tissue necrosis and inflammation.

Original languageEnglish (US)
Article numbere7446
JournalPLoS One
Volume4
Issue number10
DOIs
StatePublished - Oct 14 2009

Fingerprint

Inflammasomes
Hemolysin Proteins
hemolysins
Staphylococcus aureus
Methicillin
mice
Methicillin-Resistant Staphylococcus aureus
cells
Chemical activation
Virulence Factors
Cell death
cell death
necrosis
Cell Death
Necrosis
virulence
caspase-1
Tissue
Staphylococcal Pneumonia
HMGB1 Protein

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Staphylococcus aureus α-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. / Craven, Robin R.; Gao, Xi; Allen, Irving C.; Gris, Denis; Wardenburg, Juliane Bubeck; McElvania-TeKippe, Erin; Ting, Jenny P.; Duncan, Joseph A.

In: PLoS One, Vol. 4, No. 10, e7446, 14.10.2009.

Research output: Contribution to journalArticle

Craven, Robin R. ; Gao, Xi ; Allen, Irving C. ; Gris, Denis ; Wardenburg, Juliane Bubeck ; McElvania-TeKippe, Erin ; Ting, Jenny P. ; Duncan, Joseph A. / Staphylococcus aureus α-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. In: PLoS One. 2009 ; Vol. 4, No. 10.
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abstract = "Community Acquired Methicillin Resistant Staphylococcus aureus (CA-MRSA) causes severe necrotizing infections of the skin, soft tissues, and lungs. Staphylococcal α-hemolysin is an essential virulence factor in mouse models of CA-MRSA necrotizing pneumonia. S. aureus α-hemolysin has long been known to induce inflammatory signaling and cell death in host organisms, however the mechanism underlying these signaling events were not well understood. Using highly purified recombinant α-hemolysin, we now demonstrate that α-hemolysin activates the Nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 protein (NLRP3)-inflammasome, a host inflammatory signaling complex involved in responses to pathogens and endogenous danger signals. Non-cytolytic mutant α-hemolysin molecules fail to elicit NLRP3-inflammasome signaling, demonstrating that the responses are not due to non-specific activation of this innate immune signaling system by bacterially derived proteins. In monocyte-derived cells from humans and mice, inflammasome assembly in response to α-hemolysin results in activation of the cysteine proteinase, caspase-1. We also show that inflammasome activation by α-hemolysin works in conjunction with signaling by other CA-MRSA-derived Pathogen Associated Molecular Patterns (PAMPs) to induce secretion of pro-inflammatory cytokines IL-1β and IL-18. Additionally, α-hemolysin induces cell death in these cells through an NLRP3-dependent program of cellular necrosis, resulting in the release of endogenous pro-inflammatory molecules, like the chromatin-associated protein, High-mobility group box 1 (HMGB1). These studies link the activity of a major S. aureus virulence factor to a specific host signaling pathway. The cellular events linked to inflammasome activity have clear relevance to the disease processes associated with CA-MRSA including tissue necrosis and inflammation.",
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