Daniel Akuma (Mentor: Igor Brodsky, PhD)

"Defining Interactions between LPS and Caspase-11 in the Non-Canonical Inflammasome"

Daniel Akuma, Daniel Grubaugh and Igor Brodsky

Gram-negative sepsis is caused by the pathological immune response to lipopolysaccharide (LPS). The cardiovascular system is integral to the pathophysiology of the ensuing bacteremia and septic shock. However, despite many efforts, treatment options remain limited due to an incomplete understanding of how immune cells sense LPS. Cytosolic LPS is sensed by the cysteine protease caspase-11 (Casp11) leading to its assembly into the supramolecular complex known as the inflammasome. The Casp11 inflammasome triggers inflammatory cell death that contributes to sepsis in murine models. Yet, the structural and functional determinants of how this unique inflammasome assembles remain poorly defined. Using novel single-cell fluorescence microscopy, my preliminary data reveal that Casp11 catalytic activity and autoprocessing are required for spontaneous and LPS-induced inflammasome assembly. By elucidating these mechanisms, our studies have the potential to fundamentally change our understanding of Casp11 signaling and provide new targets for developing therapeutics against gram-negative sepsis.