title: Cross-talk between Staphylococcus aureus leukocidins-intoxicated macrophages and lung epithelial cells triggers chemokine secretion in an inflammasome-dependent manner.
abstract: Staphylococcus aureus is a major pathogen responsible for both nosocomial and community-acquired infections. Central to its virulence is its ability to secrete haemolysins, pore-forming toxins and cytolytic peptides. The large number of membrane-damaging toxins and peptides produced during S. aureus infections has hindered a precise understanding of their specific roles in diseases. Here, we used comprehensive libraries of recombinant toxins and synthetic cytolytic peptides, of S. aureus mutants and clinical strains to investigate the role of these virulence factors in targeting human macrophages and triggering IL-1β release. We found that the Panton Valentine leukocidin (PVL) is the major trigger of IL-1β release and inflammasome activation in primary human macrophages. The cytolytic peptides, δ-haemolysin and PSMα3; the pore-forming toxins, γ-haemolysin and LukDE; and β-haemolysin synergize with PVL to amplify IL-1β release, indicating that these factors cooperate with PVL to trigger inflammation. PVL(+) S. aureus causes necrotizing pneumonia in children and young adults. The severity of this disease is due to the massive recruitment of neutrophils that cause lung damage. Importantly, we demonstrate that PVL triggers IL-1β release in human alveolar macrophages. Furthermore, IL-1β released by PVL-intoxicated macrophages stimulates the secretion of the neutrophil attracting chemokines, IL-8 and monocyte chemotactic protein-1, by lung epithelial cells. Finally, we show that PVL-induced IL-8/monocyte chemotactic protein-1 release is abolished by the inclusion of IL-1 receptor antagonist (IL-1Ra) in a mixed culture of lung epithelial cells and macrophages. Together, our results identify PVL as the predominant S. aureus secreted factor for triggering inflammasome activation in human macrophages and demonstrate how PVL-intoxicated macrophages orchestrate inflammation in the lung. Finally, our work suggests that anakinra, a synthetic IL-1Ra, may be an effective therapeutic agent to reduce the massive neutrophils infiltration observed during necrotizing pneumonia and decrease the resulting host-mediated lung injury.
authors.affiliation: Université de Lyon, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Perret
authors.forename: Cédric
authors.initials: C
authors.lastname: Badiou
authors.forename: Gérard
authors.initials: G
authors.lastname: Lina
authors.forename: Sophie
authors.initials: S
authors.lastname: Burbaud
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Benito
authors.forename: Michèle
authors.initials: M
authors.lastname: Bes
authors.forename: Vincent
authors.initials: V
authors.lastname: Cottin
authors.forename: Florence
authors.initials: F
authors.lastname: Couzon
authors.forename: Carole
authors.initials: C
authors.lastname: Juruj
authors.forename: Olivier
authors.initials: O
authors.lastname: Dauwalder
authors.forename: Nadège
authors.initials: N
authors.lastname: Goutagny
authors.forename: Binh An
authors.initials: BA
authors.lastname: Diep
authors.forename: François
authors.initials: F
authors.lastname: Vandenesch
authors.forename: Thomas
authors.initials: T
authors.lastname: Henry
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism*; D002648:Child; D004847:Epithelial Cells / Q000276:immunology*; D005098:Exotoxins / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D007956:Leukocidins / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology*; D009504:Neutrophils / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology / Q000472:pathogenicity*; D037521:Virulence Factors / Q000378:metabolism; D055815:Young Adult
chemical_list: D001427:Bacterial Toxins; D018925:Chemokines; D005098:Exotoxins; D058847:Inflammasomes; D053583:Interleukin-1beta; D007956:Leukocidins; C078284:Panton-Valentine leukocidin; D037521:Virulence Factors