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.

Uropathogenic Escherichia coli (UPEC) causes urinary tract infections that can result in sepsis. Hemostasis is protective in the pyelonephritis stage of ascending UPEC infection, the role of hemostasis but has not been investigated during sepsis. Here we utilize a zebrafish-UPEC sepsis model to visualize infection-induced coagulation and examine the effects of commonly prescribed anti-hemostatic medications on the infection severity. Treatment of septic zebrafish with warfarin, aspirin, or ticagrelor reduced host survival, while stabilization of clots with aminocaproic acid increased host survival. Our findings provide evidence that commonly prescribed anti-hemostatic medications may worsen the outcome of severe UPEC infection.

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