Oral Presentation Australian Society for Microbiology Annual Scientific Meeting 2019

A multi-component toxin from Bacillus cereus activates the NLRP3 inflammasome (#31)

Anukriti Mathur 1 , Shouya Feng 1 , Jenni A. Hayward 1 , Chinh Ngo 1 , Daniel Fox 1 , Si Ming Man 1
  1. Australian National University, Acton, ACT, Australia

Recognition of microbial components by the host serves as a cornerstone in mediating an effective immune response. Innate immune sensors and the inflammasome detect both intracellular and extracellular micro-organisms. The inflammasome is an intracellular signalling complex comprising of a sensor, an adaptor protein ASC and the cysteine protease caspase-1. Inflammasomes regulate secretion of the pro-inflammatory cytokines IL-1Ī² and IL-18 and induction of a cell death pathway known as pyroptosis. A central question in the field is how extracellular bacteria are sensed by the inflammasome in the cytoplasm? To address this question, we analysed a panel of clinically important intracellular and extracellular bacteria and identified an unknown secreted factor from the foodborne bacteriumĀ Bacillus cereus that uniquely activates the inflammasome without gaining cytosolic access. The tripartite enterotoxin called haemolysin BL (HBL) was identified as the novel activator of the NLRP3 inflammasome. The multi-component toxin assembled in a specific and linear order on the mammalian cell membrane to form a lytic pore, which induces potassium efflux and activates the NLRP3 inflammasome. Furthermore, HBL-producing B. cereus induced rapid lethality in host within 20h of infection via activation of the NLRP3 inflammasome. B. cereus-induced lethality was completely abrogated with administration of the NLRP3 inhibitor, MCC950. Overall, our results indicate that intracellular sensing of a toxin secreted by an extracellular bacterium is critical for the innate immune recognition of infection. Therapeutic modulation of the inflammasome can facilitate in prevention and treatment of fulminant bacterial infections.