TY - JOUR T1 - OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202201476 VL - 5 IS - 9 SP - e202201476 AU - Elinor Hortle AU - Vi LT Tran AU - Kathryn Wright AU - Angela RM Fontaine AU - Natalia Pinello AU - Matthew B O’Rourke AU - Justin J-L Wong AU - Philip M Hansbro AU - Warwick J Britton AU - Stefan H Oehlers Y1 - 2022/09/01 UR - https://www.life-science-alliance.org/content/5/9/e202201476.abstract N2 - Pathogenic mycobacteria inhibit inflammasome activation to establish infection. Although it is known that potassium efflux is a trigger for inflammasome activation, the interaction between mycobacterial infection, potassium efflux, and inflammasome activation has not been investigated. Here, we use Mycobacterium marinum infection of zebrafish embryos and Mycobacterium tuberculosis infection of THP-1 cells to demonstrate that pathogenic mycobacteria up-regulate the host WNK signalling pathway kinases SPAK and OXSR1 which control intracellular potassium balance. We show that genetic depletion or inhibition of OXSR1 decreases bacterial burden and intracellular potassium levels. The protective effects of OXSR1 depletion are at least partially mediated by NLRP3 inflammasome activation, caspase-mediated release of IL-1β, and downstream activation of protective TNF-α. The elucidation of this druggable pathway to potentiate inflammasome activation provides a new avenue for the development of host-directed therapies against intracellular infections. ER -