KCC1 Activation protects Mice from the Development of Experimental Cerebral Malaria

Hortle, Elinor; Starrs, Lora; Brown, Fiona C.; Jane, Stephen M.; Curtis, David; McMorran, Brendan J.; Foote, Simon J.; Burgio, Gaétan

doi:10.1038/s41598-019-42782-x

Cited by 6 publications

(5 citation statements)

References 41 publications

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“…We have further shown that constitutively active KCC1 alters the inflammatory response to malaria infection in mice, and that this effect is associated with dramatically increased survival 27 . Here we sought to investigate whether the SPAK/OXSR1 pathway is involved in the host response to mycobacterial infection, and if this pathway could be manipulated as a hostdirected therapy against infection.…”

Section: Introductionmentioning

confidence: 67%

OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection

Hortle

et al. 2021

Preprint

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Pathogenic 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 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.

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Section: Introductionmentioning

confidence: 67%

OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection

Hortle

et al. 2021

Preprint

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“…Indeed, a contemporary article has demonstrated WNK1 deficiency potentiates NLRP3 inflammasome activation in mice (Mayes-Hopfinger et al, 2021). We have further shown that constitutively active KCC1 alters the inflammatory response to malaria infection in mice, and that this effect is associated with dramatically increased survival (Hortle et al, 2019b). Here we sought to investigate whether the SPAK/OXSR1 pathway is involved in the host response to mycobacterial infection, and if this pathway could be manipulated as a host-directed therapy against infection.…”

Section: Introductionmentioning

confidence: 80%

OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection

et al. 2022

Self Cite

View full text Add to dashboard Cite

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.

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“…The correlation between RBC dehydration and hemolysis in PIEZO E756del activated RBC suggests the following mechanism of protection of PIEZO1 E756del carriers from severe forms of malaria: gain of function PIEZO1 E756del becomes activated by shear stress and leads to increased RBC dehydration that, in turn, leads to increased RBC hemolysis and inefficient parasite replication. More generally, cell dehydration could emerge as a factor associated with the amelioration of malaria both in malaria patients and in rodent malaria models due to i) sickle hemoglobin, 30,31,45 ii) deficiency in PMCA4 production, 46 iii) gain of function KCC1 co-transporter 47-48 and iv) gain of function PIEZO1 E756del . 3,7 Further investigations into the protective mechanisms of erythrocyte dehydration and erythrocyte membrane pathology on malaria parasite biology and malaria pathogenesis is warranted.…”

Section: Discussionmentioning

confidence: 99%

PIEZO1-dependent erythrocyte dehydration as the mechanism for selection of an allele protecting from severe malaria

Zimmerberg

Glushakova

Bezrukov

et al. 2022

Preprint

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PIEZO1 is a cation specific mechanoreceptor channel implicated in red blood cell (RBC) volume homeostasis. Several PIEZO1 gain of function (GoF) variants demonstrate delayed channel inactivation and can cause hereditary xerocytosis (HX), a disease characterized by hemolytic anemia, RBC dehydration, and shape distortion. The milder PIEZO1E756del GoF variant, prevalent in populations of African descent, protects carriers from severe malaria caused by Plasmodium falciparum and ameliorate disease in a rodent malaria model. To explore the mechanism of this malaria protection, P. falciparum infection of human PIEZO1E756del RBC was analyzed in shear-stressed and static cultures with and without Yoda1, a PIEZO1 agonist. RBC dehydration was a common pathophysiological factor affecting parasite replication in both culture conditions. PIEZO1 channel opening by either Yoda1 or shear stress produced dehydration-dependent cell hemolysis, inhibiting P. falciparum infection. Since the physiological activator of PIEZO1 in circulating RBC is shear stress, we propose that shear stress-induced dehydration, disproportionally affecting RBC of GoF PIEZO1 E756del carriers, makes erythrocytes less habitable for P. falciparum to the point of hemolysis, and thus ameliorates malaria in GoF PIEZO1E756del carriers. More generally, RBC dehydration processes may be a pathway for protection from the severe form of malaria common to several hematological disorders, including sickle cell trait.

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KCC1 Activation protects Mice from the Development of Experimental Cerebral Malaria

Cited by 6 publications

References 41 publications

OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection

OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection

OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection

PIEZO1-dependent erythrocyte dehydration as the mechanism for selection of an allele protecting from severe malaria

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