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

Andreas Greth, Shelley Lampkin, Preethi Mayura-Guru, Fleur Rodda, Karen Drysdale, Meredith Roberts-Thomson, Brendan J. McMorran, Simon J. Foote, Gaétan Burgio*

*Corresponding author for this work

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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.

Original languageEnglish
Article numbere38999
Pages (from-to)1-13
Number of pages13
JournalPLoS ONE
Volume7
Issue number6
DOIs
Publication statusPublished - 19 Jun 2012

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Copyright the Author(s) [2012]. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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    Greth, A., Lampkin, S., Mayura-Guru, P., Rodda, F., Drysdale, K., Roberts-Thomson, M., ... Burgio, G. (2012). A novel ENU-mutation in Ankyrin-1 disrupts malaria parasite maturation in red blood cells of mice. PLoS ONE, 7(6), 1-13. [e38999]. https://doi.org/10.1371/journal.pone.0038999