Abstract
AbstractThe factors that determine red blood cell (RBC) lifespan and the rate of RBC aging have not been fully elucidated. In several genetic conditions, including sickle cell disease, thalassemia, and G6PD deficiency, erythrocyte lifespan is significantly shortened. Many of these diseases are also associated with protection from severe malaria, suggesting a role for accelerated RBC senescence and clearance in malaria resistance. Here, we report a novel, N-ethyl-N-nitrosourea–induced mutation that causes a gain of function in adenosine 5′-monophosphate deaminase (AMPD3). Mice carrying the mutation exhibit rapid RBC turnover, with increased erythropoiesis, dramatically shortened RBC lifespan, and signs of increased RBC senescence/eryptosis, suggesting a key role for AMPD3 in determining RBC half-life. Mice were also found to be resistant to infection with the rodent malaria Plasmodium chabaudi. We propose that resistance to P. chabaudi is mediated by increased RBC turnover and higher rates of erythropoiesis during infection.
Highlights
The factors that determine red blood cell (RBC) lifespan and the rate of RBC aging have not been fully elucidated
In screen looking for dominant ENU-induced novel malaria/red cell phenotypes, we identified a G1 animal (MRI49372) with leukocytosis, thrombocytosis, reticulocytosis, macrocytosis, and anisocytosis, accompanied by moderate anemia
The reticulocytes level was unchanged for WT but altered for both splenectomized mutants; reticulocyte levels remained steady in Ampd3T689A/1 splenectomized mice and fell from 43% to 19% in splenectomized Ampd3T689A mice (Figure 7D). These results show that nonsplenectomized Ampd3T689A/1 mice are able to increase erythropoiesis in response to P. chabaudi infection and the nonsplenectomized Ampd3T689A mice reticulocytosis level remained high throughout the course of the infection
Summary
The factors that determine red blood cell (RBC) lifespan and the rate of RBC aging have not been fully elucidated. In several genetic conditions, including sickle cell disease, thalassemia, and G6PD deficiency, erythrocyte lifespan is significantly shortened. Many of these diseases are associated with protection from severe malaria, suggesting a role for accelerated RBC senescence and clearance in malaria resistance. Mice carrying the mutation exhibit rapid RBC turnover, with increased erythropoiesis, dramatically shortened RBC lifespan, and signs of increased RBC senescence/eryptosis, suggesting a key role for AMPD3 in determining RBC half-life. We propose that resistance to P. chabaudi is mediated by increased RBC turnover and higher rates of erythropoiesis during infection. We propose that resistance to P. chabaudi is mediated by increased RBC turnover and higher rates of erythropoiesis during infection. (Blood. 2016; 128(9):1290-1301)
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