title: Adenosine monophosphate deaminase 3 activation shortens erythrocyte half-life and provides malaria resistance in mice.
abstract: 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 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.
authors.affiliation: Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia;
authors.forename: Elinor
authors.initials: E
authors.lastname: Hortle
authors.affiliation: Metabolomics Australia, Bio21 Institute, University of Melbourne, Parkville, VIC, Australia;
authors.forename: Brunda
authors.initials: B
authors.lastname: Nijagal
authors.affiliation: Commonwealth Scientific and Industrial Research Organization, Sydney, NSW, Australia;
authors.forename: Denis C
authors.identifier: 0000-0001-8033-9810
authors.initials: DC
authors.lastname: Bauer
authors.affiliation: Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia;
authors.forename: Lora M
authors.initials: LM
authors.lastname: Jensen
authors.affiliation: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia; and.
authors.forename: Seong Beom
authors.initials: SB
authors.lastname: Ahn
authors.affiliation: Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia;
authors.forename: Ian A
authors.initials: IA
authors.lastname: Cockburn
authors.affiliation: Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia;
authors.forename: Shelley
authors.initials: S
authors.lastname: Lampkin
authors.affiliation: Metabolomics Australia, Bio21 Institute, University of Melbourne, Parkville, VIC, Australia;
authors.forename: Dedreia
authors.initials: D
authors.lastname: Tull
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: McConville
authors.affiliation: Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia;
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: McMorran
authors.affiliation: Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia;
authors.forename: Simon J
authors.identifier: 0000-0002-9142-2107
authors.initials: SJ
authors.lastname: Foote
authors.affiliation: Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia;
authors.forename: Gaetan
authors.identifier: 0000-0002-7434-926X
authors.initials: G
authors.lastname: Burgio
mesh_terms: D000659:AMP Deaminase / Q000235:genetics / Q000276:immunology; D000818:Animals; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology; D004912:Erythrocytes / Q000276:immunology* / Q000469:parasitology; D004920:Erythropoiesis / Q000235:genetics / Q000276:immunology; D005038:Ethylnitrosourea / Q000633:toxicity; D006207:Half-Life; D007113:Immunity, Innate; D008288:Malaria / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D009154:Mutation; D016788:Plasmodium chabaudi / Q000276:immunology*
chemical_list: D000659:AMP Deaminase; C579174:AMPD3 protein, mouse; D005038:Ethylnitrosourea