Microbial activators of the inflammasome

Abstract

Innate immune recognition of microbial components serves as a cornerstone in mediating an effective immune response. Innate immune sensors and inflammasomes detect both intracellular and extracellular microorganisms. The inflammasome is an intracellular signalling complex comprising of a sensor, an adaptor protein ASC (known as apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) and the cysteine protease caspase-1. Inflammasomes regulate secretion of the pro-inflammatory cytokines, IL-1β and IL-18, and induction of a cell death pathway known as pyroptosis. Certain intracellular bacteria require cytosolic access to activate the inflammasome, however, how extracellular bacteria are sensed by the inflammasome in the cytoplasm remains largely unclear. To understand the innate immune recognition of extracellular bacteria, a panel of clinically important intracellular and extracellular bacteria were analysed. This analysis led to the identification of an unknown secreted factor from the foodborne bacterium Bacillus cereus that activated the inflammasome without gaining cytosolic access. The tripartite enterotoxin called haemolysin BL (HBL) was identified as the novel activator of the NLRP3 inflammasome. I further identified another tripartite toxin called non-haemolytic enterotoxin (NHE), which also activated NLRP3 to induce inflammation and cell death. Mechanistically, both multi-component toxins assembled in a specific and linear order on the mammalian plasma membrane to form a lytic pore, which induces potassium efflux. Remarkably, HBL and NHE operated synergistically to drive inflammation in a mouse model of B. cereus infection. Administration of a small molecule NLRP3 inhibitor MCC950 inhibited inflammation induced by HBL and NHE in vivo and rescued mice from B. cereus-induced lethality. These data showcase the ability of a single inflammasome sensor to detect structurally and functionally similar toxins from the same bacterium. Overall, this research identified novel activators of the inflammasome and their molecular mechanisms in activating inflammation and cell death responses. Understanding the molecular basis of host-pathogen interactions has the potential to contribute therapies which target microbial virulence factors and/or the immune system in the treatment of infectious diseases.