Daniel Bachovchin

The innate immune system uses germline-encoded receptors to detect and respond to pathogens.  At least six human innate immune receptors recognize specific pathogen-associated danger signals and assemble into multi-protein complexes called inflammasomes (Figure 1).  Inflammasomes recruit and activate inflammatory caspases, thereby triggering a lytic form of cell death called pyroptosis.  Pyroptosis is perhaps the most dramatic, powerful, and pro-inflammatory response a cell can execute, and thus the signals that activate inflammasomes must be among the most dangerous in human biology.  Despite their extraordinary importance, however, the identities of several of these danger signals, and how they activate their respective inflammasomes, have yet to be fully established.   

Fig. 1.  Inflammasome activation.  Certain pathogen-associated danger signals activate sensor proteins to form inflammasomes.  Inflammasomes activate caspase-1, which in turn cleaves and activates pro-inflammatory cytokines and gasdermin D (GSDMD).  GSDMD forms pores in the cell membrane, releasing the activated cytokines and inducing a lytic form of cell death called pyroptosis. 

As a chemical biology lab, we entered the inflammasome field in an unusual way – via investigations into the intriguing immunostimulatory activity of the small molecule Val-boroPro (VbP).  VbP is a non-selective inhibitor of the post-proline cleaving serine proteases that induces immune-mediated tumor regressions in multiple mouse models of cancer.  Although VbP’s anti-cancer activity was first identified more than twenty years ago, its mechanism of action was essentially unknown.  We anticipated that characterization of VbP’s mechanism of action would be highly significant because it would reveal new fundamental mechanisms regulating mammalian immune systems and identify new targets and strategies for cancer immunotherapy. Shortly after starting my lab, we discovered that VbP stimulates immune systems by activating the related NLRP1 and CARD8 inflammasomes.  Prior to this discovery, very little was known about the NLRP1 and CARD8 inflammasomes, including, most importantly, the identities of the danger signals that they detect.  Over the past eight years, we have made considerable progress in characterizing these two innate immune receptors, as well as in delineating mechanisms that control inflammasome signaling in general.  My lab is now working to fully understand, and eventually to therapeutically harness, the activation of the NLRP1 and CARD8 inflammasomes.