OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection

Abstract

SummaryPathogenic mycobacteria inhibit inflammasome activation as part of their pathogenesis. While 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 of human THP-1 cells to demonstrate that pathogenic mycobacteria upregulate 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 mediated by NLRP3 inflammasome activation and are dependent on caspase-mediated release of IL-1β and the 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.