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Erythrocyte β spectrin can be genetically targeted to protect mice from malaria

Patrick M. Lelliott, Hong Ming Huang, Matthew W. Dixon, Arman Namvar, Adam J. Blanch, Vijay Rajagopal, Leann Tilley, Cevayir Coban, Brendan J. McMorran, Simon J. Foote and Gaetan Burgio

Key Points

  • Mutations in β spectrin cause microcytosis, resulting in increased clearance of erythrocytes and enhanced resistance to malaria in mice.

  • A homozygous CRISPR/Cas9-induced mutation in the binding site between β spectrin and ankyrin-1 increases mouse survival during malaria.

Abstract

The malaria parasite hijacks host erythrocytes to shield itself from the immune system and proliferate. Red blood cell abnormalities can provide protection from malaria by impeding parasite invasion and growth within the cell or by compromising the ability of parasites to avoid host clearance. Here, we describe 2 N-ethyl-N-nitrosourea–induced mouse lines, SptbMRI26194 and SptbMRI53426, containing single-point mutations in the erythrocyte membrane skeleton gene, β spectrin (Sptb), which exhibit microcytosis but retain a relatively normal ratio of erythrocyte surface area to volume and are highly resistant to rodent malaria. We propose the major factor responsible for malaria protection is the specific clearance of mutant erythrocytes, although an enhanced clearance of uninfected mutant erythrocytes was also observed (ie, the bystander effect). Using an in vivo erythrocyte tracking assay, we established that this phenomenon occurs irrespective of host environment, precluding the involvement of nonerythrocytic cells in the resistance mechanism. Furthermore, we recapitulated this phenotype by disrupting the interaction between ankyrin-1 and β spectrin in vivo using CRISPR/Cas9 genome editing technology, thereby genetically validating a potential antimalarial target. This study sheds new light on the role of β spectrin during Plasmodium infection and highlights how changes in the erythrocyte cytoskeleton can substantially influence malaria susceptibility with minimal adverse consequences for the host.

  • Submitted June 8, 2017.
  • Accepted October 31, 2017.
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