Dr Josh Ang - Ang Group and Dr Davey Kneafsey: Boucher lab - University of York

Speaker: Dr Josh Ang

Daisy chain gene drive for localised control of the urban malaria vector Anopheles stephensi

Speaker: Dr Davey Kneafsey, PDRA in the Boucher lab

When Caspases Don’t Cut It: Caspase-Independent Intracellular LPS Sensing

Innate immunity is the body’s initial response to infection, acting rapidly to suppress pathogen growth and promoting the subsequent activation of adaptive responses.  Many innate responses are triggered through the recognition of common epitopes found on pathogens, known as pathogen-associated molecular patterns (PAMPs).  One such PAMP is the lipopolysaccharide (LPS) of Gram-negative bacteria. LPS is sensed intracellularly by human cells through the noncanonical inflammasome pathway, leading to activation of caspase-4. Active caspase-4 acts as a protease, cleaving and activating substrates such as inflammatory cytokines and the pore-forming protein gasdermin D. This triggers a highly inflammatory form of lytic cell death known as pyroptosis. While inflammation is essential for mounting protective immune responses, overactivation of inflammatory pathways can lead to
inflammatory disease. These conditions are associated with severe morbidity and mortality, such as sepsis contributing to an estimated 20% of deaths worldwide.  Using integrated transcriptomic and proteomic analyses supported by molecular assays, we identify a previously unrecognized regulatory response to intracellular LPS that acts as a backup mechanism upon caspase-4 inhibition or absence. We term this the Caspase-Independent Intracellular LPS Response (CIILR). The absence of caspase-4 activity can arise during infection with pathogens that actively inhibit it, such as Shigella and with caspase-4 inhibitors used in the treatment of inflammatory conditions. Understanding how human cells respond in the absence of caspase-4 will inform future strategies in the treatment of both bacterial infections and inflammatory disease.