期刊
BLOOD
卷 128, 期 9, 页码 1290-1301出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-09-666834
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资金
- National Health and Medical Research Council of Australia [490037, 605524, APP1047090]
- Australian Society for Parasitology, OzEMalaR, National Collaborative Research Infrastructure Strategy
- Education Investment Fund from the Department of Education and Training
- Australian Phenomics Network
- Howard Hughes Medical Institute
- Bill and Melinda Gates Foundation
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 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 59-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.
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