Common PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection

Abstract

Hereditary xerocytosis is thought to be a rare genetic condition characterized by red blood cell (RBC) dehydration with mild hemolysis. RBC dehydration is linked to reduced Plasmodium infection in vitro; however, the role of RBC dehydration in protection against malaria in vivo is unknown. Most cases of hereditary xerocytosis are associated with gain-of-function mutations in PIEZO1, a mechanically activated ion channel. We engineered a mouse model of hereditary xerocytosis and show that Plasmodium infection fails to cause experimental cerebral malaria in these mice due to the action of Piezo1 in RBCs and in T cells. Remarkably, we identified a novel human gain-of-function PIEZO1 allele, E756del, present in a third of the African population. RBCs from individuals carrying this allele are dehydrated and display reduced Plasmodium infection in vitro. The existence of a gain-of-function PIEZO1 at such high frequencies is surprising and suggests an association with malaria resistance.

TACAN is an essential component of the mechanosensitive ion channel responsible for pain sensing

“…Much like the Piezo family of MSC, which was found to be involved in touch (Ranade et al, 2014b), proprioception (Woo et al, 2015), lung inflation (Nonomura et al, 2017), vascular development (Ranade et al, 2014a), and red blood cell volume regulation (Cahalan et al, 2015;Ma et al, 2018), TACAN is expressed in many tissues and likely to play important roles in several mechanotransduction processes. TACAN also has a homolog in mammalian cells, TMEM120B, but its heterologous expression did not increase mechanically-evoked currents ( Figure S6).…”

A common polymorphism in the druggable ion channel PIEZO1 is associated with protection from severe malaria

“…Using a comparative genomics approach, a common PIEZO1 polymorphism was 49 identified in healthy individuals of African descent that may be under positive selection and act as 50 a gain-of-function allele (MA et al 2018). The mutation, E756del (rs572934641), is a 3 nucleotide 51 deletion in a coding region of the gene that includes ~60 bp of short tandem repeats.…”

“…E756del was classified as a gain-of-function mutant based on studies in HEK cells, where it 53 displayed a prolonged inactivation time constant after mechanical stimulation as compared to 54 wild-type PIEZO1. Results from in vitro assays using the human malaria parasite P. falciparum 55 suggested that parasite growth was impaired in RBCs from E756del heterozygotes as compared 56 to wild-type RBCs (MA et al 2018). Together, these findings raise the intriguing possibility that 57 the PIEZO1 E756del allele may be protective against severe malaria in humans.…”

“…E756del heterozygous RBCs could be that E756del confers only a mild channel defect. Indeed, 386 out of two candidates and one established PIEZO1 GOF mutation tested, E756del displayed the 387 shortest channel inactivation time (MA et al 2018). As the experiments measuring channel 388 kinetics were performed using ectopic expression in HEK cells, it is possible that the channel 389 phenotype of E756del in heterozygous RBCs is even more mild.…”

Circulating cell‐free DNA and ineffective erythropoiesis in nontransfusion‐dependent β‐thalassemia

“…Small amounts of cfDNA are detectable in plasma of healthy individuals, while increased levels are observed in pathologic conditions, including cancer, trauma, stroke, chronic inflammation and infection, myocardial ischemia, and autoimmune diseases, proportionally to clinical severity. 1 Hematopoietic cells are likely to contribute to a certain amount of measurable cfDNA, being in close contact with the plasma moiety.…”