Journal
BLOOD ADVANCES
Volume 1, Issue 26, Pages 2624-2636Publisher
ELSEVIER
DOI: 10.1182/bloodadvances.2017009274
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Funding
- National Health and Medical Research Council [APP605524, 490037, 1047082]
- Australian Research Council [DP12010061, FL150100106]
- National Collaborative Research Infrastructure Strategy of Australia
- Department of Innovation, Industry, Science and Research via the Australian Phenomics Network
- Japan Society for the Promotion of Science Fellowship Program [S16706]
- Australian postgraduate award
- Australian Research Council [FL150100106] Funding Source: Australian Research Council
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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, Sptb(MRI26194) and Sptb(MRI53426), containing single-point mutations in the erythrocyte membrane skeleton gene, beta 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 beta 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 beta spectrin during Plasmodium infection and highlights how changes in the erythrocyte cytoskeleton can substantially influence malaria susceptibility with minimal adverse consequences for the host.
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