A multicomponent toxin from Bacillus cereus incites inflammation and shapes host outcome via the NLRP3 inflammasome.
Animals
Bacillus cereus
/ immunology
Bacterial Proteins
/ immunology
Cell Membrane
/ metabolism
Cells, Cultured
Culture Media, Conditioned
Enterotoxins
/ chemistry
Female
Hemolysin Proteins
/ immunology
Immunity, Innate
Inflammasomes
/ metabolism
Inflammation
Macrophages
/ immunology
Male
Mice
Mice, Mutant Strains
NLR Family, Pyrin Domain-Containing 3 Protein
/ antagonists & inhibitors
Potassium
/ metabolism
Protein Multimerization
Pyroptosis
Survival Analysis
Journal
Nature microbiology
ISSN: 2058-5276
Titre abrégé: Nat Microbiol
Pays: England
ID NLM: 101674869
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
30
06
2018
accepted:
07
11
2018
pubmed:
12
12
2018
medline:
28
5
2019
entrez:
12
12
2018
Statut:
ppublish
Résumé
Host recognition of microbial components is essential in mediating an effective immune response. Cytosolic bacteria must secure entry into the host cytoplasm to facilitate replication and, in doing so, liberate microbial ligands that activate cytosolic innate immune sensors and the inflammasome. Here, we identified a multicomponent enterotoxin, haemolysin BL (HBL), that engages activation of the inflammasome. This toxin is highly conserved among the human pathogen Bacillus cereus. The three subunits of HBL bind to the cell membrane in a linear order, forming a lytic pore and inducing activation of the NLRP3 inflammasome, secretion of interleukin-1β and interleukin-18, and pyroptosis. Mechanistically, the HBL-induced pore results in the efflux of potassium and triggers the activation of the NLRP3 inflammasome. Furthermore, HBL-producing B. cereus induces rapid inflammasome-mediated mortality. Pharmacological inhibition of the NLRP3 inflammasome using MCC950 prevents B. cereus-induced lethality. Overall, our results reveal that cytosolic sensing of a toxin is central to the innate immune recognition of infection. Therapeutic modulation of this pathway enhances host protection against deadly bacterial infections.
Identifiants
pubmed: 30531979
doi: 10.1038/s41564-018-0318-0
pii: 10.1038/s41564-018-0318-0
pmc: PMC7685251
mid: NIHMS1625636
doi:
Substances chimiques
Bacterial Proteins
0
Culture Media, Conditioned
0
Enterotoxins
0
Hemolysin Proteins
0
Inflammasomes
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
Nlrp3 protein, mouse
0
hemolysin BL protein, Bacillus
0
Potassium
RWP5GA015D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
362-374Subventions
Organisme : Intramural NIH HHS
ID : ZIA AI001030
Pays : United States
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