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A novel ENU-mutation in ankyrin-1 disrupts malaria parasite maturation in red blood cells of mice

Citation

Greth, A and Lampkin, S and Mayura-Guru, P and Rodda, F and Drysdale, K and Roberts-Thomson, M and McMorran, BJ and Foote, SJ and Burgio, G, A novel ENU-mutation in ankyrin-1 disrupts malaria parasite maturation in red blood cells of mice, PLoS One, 7, (6) Article e38999. ISSN 1932-6203 (2012) [Refereed Article]


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Licenced under Creative Commons Attribution 2.5 Generic (CC BY 2.5) http://creativecommons.org/licenses/by/2.5/

DOI: doi:10.1371/journal.pone.0038999

Abstract

The blood stage of the plasmodium parasite life cycle is responsible for the clinical symptoms of malaria. Epidemiological studies have identified coincidental malarial endemicity and multiple red blood cell (RBC) disorders. Many RBC disorders result from mutations in genes encoding cytoskeletal proteins and these are associated with increased protection against malarial infections. However the mechanisms underpinning these genetic, host responses remain obscure. We have performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen and have identified a novel dominant (haploinsufficient) mutation in the Ank-1 gene (Ank1MRI23420) of mice displaying hereditary spherocytosis (HS). Female mice, heterozygous for the Ank-1 mutation showed increased survival to infection by Plasmodium chabaudi adami DS with a concomitant 30% decrease in parasitemia compared to wild-type, isogenic mice (wt). A comparative in vivo red cell invasion and parasite growth assay showed a RBC-autonomous effect characterised by decreased proportion of infected heterozygous RBCs. Within approximately 6-8 hours post-invasion, TUNEL staining of intraerythrocytic parasites, showed a significant increase in dead parasites in heterozygotes. This was especially notable at the ring and trophozoite stages in the blood of infected heterozygous mutant mice compared to wt (p<0.05). We conclude that increased malaria resistance due to ankyrin-1 deficiency is caused by the intraerythrocytic death of P. chabaudi parasites.

Item Details

Item Type:Refereed Article
Keywords:Plasmodium chabaudi, trophozoite, ankyrin, ankyrin 1, ethylnitrosourea, gene, erythrocyte, haploinsufficiency, ereditary spherocytosis, heterozygosity, infection resistance, malaria, mutagenesis, parasitemia
Research Division:Medical and Health Sciences
Research Group:Cardiorespiratory Medicine and Haematology
Research Field:Haematology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Blood Disorders
Author:Greth, A (Mr Andreas Greth)
Author:Lampkin, S (Miss Shelley Lampkin)
Author:Mayura-Guru, P (Mrs Preethi Mayura Guru)
Author:Rodda, F (Miss Fleur Rodda)
Author:Drysdale, K (Ms Karen Drysdale)
Author:Roberts-Thomson, M (Ms Meredith Roberts-Thomson)
Author:McMorran, BJ (Dr Brendan McMorran)
Author:Foote, SJ (Professor Simon Foote)
Author:Burgio, G (Dr Gaetan Burgio)
ID Code:79226
Year Published:2012
Funding Support:National Health and Medical Research Council (605524)
Web of Science® Times Cited:21
Deposited By:Menzies Institute for Medical Research
Deposited On:2012-08-28
Last Modified:2017-11-06
Downloads:390 View Download Statistics

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