title: A novel ENU-induced ankyrin-1 mutation impairs parasite invasion and increases erythrocyte clearance during malaria infection in mice.
abstract: Genetic defects in various red blood cell (RBC) cytoskeletal proteins have been long associated with changes in susceptibility towards malaria infection. In particular, while ankyrin (Ank-1) mutations account for approximately 50% of hereditary spherocytosis (HS) cases, an association with malaria is not well-established, and conflicting evidence has been reported. We describe a novel N-ethyl-N-nitrosourea (ENU)-induced ankyrin mutation MRI61689 that gives rise to two different ankyrin transcripts: one with an introduced splice acceptor site resulting a frameshift, the other with a skipped exon. Ank-1(MRI61689/+)mice exhibit an HS-like phenotype including reduction in mean corpuscular volume (MCV), increased osmotic fragility and reduced RBC deformability. They were also found to be resistant to rodent malaria Plasmodium chabaudi infection. Parasites in Ank-1(MRI61689/+)erythrocytes grew normally, but red cells showed resistance to merozoite invasion. Uninfected Ank-1(MRI61689/+)erythrocytes were also more likely to be cleared from circulation during infection; the "bystander effect". This increased clearance is a novel resistance mechanism which was not observed in previous ankyrin mouse models. We propose that this bystander effect is due to reduced deformability of Ank-1(MRI61689/+)erythrocytes. This paper highlights the complex roles ankyrin plays in mediating malaria resistance.
authors.affiliation: Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, ACT, Australia.
authors.forename: Hong Ming
authors.initials: HM
authors.lastname: Huang
authors.affiliation: CSIRO, Sydney, NSW, Australia.
authors.forename: Denis C
authors.initials: DC
authors.lastname: Bauer
authors.affiliation: IFReC Research Building, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Lelliott
authors.affiliation: synaps studios GmbH, Rebmoosweg 73A, CH-5200 Brugg, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Greth
authors.affiliation: Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, 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, ACT, Australia.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Foote
authors.affiliation: Department of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, ACT, Australia.
authors.forename: Gaetan
authors.initials: G
authors.lastname: Burgio
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D017487:Ankyrins / Q000235:genetics*; D004907:Erythrocyte Deformability / Q000187:drug effects; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D005038:Ethylnitrosourea / Q000633:toxicity*; D006790:Host-Parasite Interactions; D008288:Malaria / Q000235:genetics / Q000469:parasitology*; D052940:Merozoites / Q000502:physiology; D051379:Mice; D009154:Mutation / Q000187:drug effects*; D016788:Plasmodium chabaudi / Q000502:physiology*
chemical_list: D000477:Alkylating Agents; C491707:Ank1 protein, mouse; D017487:Ankyrins; D005038:Ethylnitrosourea