Defining human and mouse non-canonical inflammasome responses to LPS

Gram-negative bacterial infections cause more than 325,000 cases of severe sepsis in the US and almost 10 million cases worldwide annually, with a >30% mortality rate. Gram-negative bacterial sepsis is caused by a dysregulated systemic inflammatory response to lipopolysaccharide (LPS) that is sensed at the plasma membrane by Toll Like Receptor 4 (TLR4) and in the cytosol by caspase-11 (CASP11) in mice, and its orthologs caspases-4 and -5 (CASP4 and CASP5) in humans. CASP11, CASP4, and CASP5 oligomerize into non- canonical inflammasomes in response to LPS, leading to pyroptotic cell death and release of inflammatory mediators. While excessive CASP11 activation during systemic LPS delivery or bacteremia can lead to sepsis, CASP11 is also essential for anti-bacterial defense against gram-negative bacterial infections in mouse models. Bacterial pathogens can vary the acylation status of LPS to evade innate immune sensing by TLR4 and CASP11. Intriguingly, recent findings by us and others indicate that human CASP4/5 are activated by LPS structures that are not sensed by TLR4 and CASP11, indicating that humans have evolved to respond to a broader repertoire of LPS structures than mice. The mechanisms dictating the differential responsiveness of CASP11 and CASP4/5 to distinct alterations in LPS structure and the consequences for host defense and sepsis are poorly understood. Thus, we propose to define the molecular and cellular mechanisms of non-canonical inflammasome responses to LPS in mice and humans using a combination of in vitro and in vivo models. This fundamental information will provide essential insight for the development of improved therapeutics that effectively reduce human sepsis, as well as immune adjuvants that improve host responses to immunoevasive bacterial pathogens. Project Number: 1R01AI194573-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Sunny Shin (+1 co-PI) | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $3,204,624 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 IIDB-P (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19457301