Program Description
Bacillus anthracis produces two toxins with a common receptor binding component. Edema toxin (ET) is an adenylate cyclase. Lethal toxin (LT) is a protease that cleaves several mitogen-activated protein kinase kinases (MEKs/MKKs) and the regulatory subunits of phosphoinositide 3-kinase (p85-alpha, p85-beta), impacting signaling pathways which are central to cell survival, proliferation, stress response, metabolism and other essential functions. LT also cleaves and activates rodent inflammasome sensor NLRP1, resulting in downstream caspase-1 and gasdermin cleavage, followed by rapid cell death (pyroptosis).

Caspase-1 activation, which also occurs through activation of other inflammasome sensors, including the NLRP3, NAIP/NLRC4, and AIM2 sensors, initiates an innate immune response through maturation and release of the pro-inflammatory cytokines IL-1β and IL-18. Rat NLRP1 is also activated by Toxoplasma gondii, and controls disease sensitivity in this mode, but the mechanism for activation is currently unknown. My primary interests are understanding the signaling pathways targeted by anthrax toxins in cell and animal models. Our studies on anthrax toxin activation of NLRP1, shutdown of MEK signaling, modulation of PI3K/Akt signaling and dysregulation of cAMP signaling provide insight into disease pathogenesis, as well as aid in better understanding these important signaling pathways. Identification of novel toxin targets, new PAMPs and DAMPs which can activate the NLRP1 inflammasome, host genetic factors which control inflammasome-mediated responses, and anti-inflammatory or anti-anthrax therapeutics are areas of active study.