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Genet Vaccines Ther. 2012 Aug 31;10(1):8. doi: 10.1186/1479-0556-10-8.

Targeting wild-type Erythrocyte receptors for Plasmodium falciparum and vivax Merozoites by Zinc Finger Nucleases In- silico: Towards a Genetic Vaccine against Malaria.

Author information

  • 1Dept of Medical Microbiology, School of Biomedical Science, College of Health Sciences, Makerere University, P O Box 7072, Kampala, Uganda. wmisaki@yahoo.com.

Abstract

BACKGROUND:

Malaria causes immense human morbidity and mortality globally. The plasmodium species vivax and falciparum cause over 75 % clinical malaria cases. Until now, gene-based strategies against malaria have only been applied to plasmodium species and their mosquito-vector. Merozoites of these two respective plasmodium species target and invade red blood cells (RBCs) by using the duffy antigen receptor for chemokines (DARC), and Sialic Acid (SLC4A1) residues of the O-linked glycans of Glycophorin A. RBCs of naturally selected duffy-negative blacks are resistant to P.vivax tropism. We hypothesized that artificial aberration of the host-pathway by target mutagenesis of either RBC -receptors, may abolish or reduce susceptibility of the host to malaria. As a first step towards the experimental actualization of these concepts, we aimed to identify zinc finger arrays (ZFAs) for constructing ZFNs that target genes of either wild-type host-RBC- receptors.

METHODS:

In-Silico Gene & Genome Informatics

RESULTS:

Using the genomic contextual nucleotide-sequences of homo-sapiens darc and glycophorin-a, and the ZFN-consortia software- CoDA-ZiFiT-ZFA and CoDA-ZiFiT-ZFN: we identified 163 and over 1,000 single zinc finger arrays (sZFAs) that bind sequences within the genes for the two respective RBC-receptors. Second, 2 and 18 paired zinc finger arrays (pZFAs) that are precursors for zinc finger nucleases (ZFNs) capable of cleaving the genes for darc and glycophorin-a were respectively assembled. Third, a mega-BLAST evaluation of the genome-wide cleavage specificity of this set of ZFNs was done, revealing alternate homologous nucleotide targets in the human genome other than darc or glycophorin A.

CONCLUSIONS:

ZFNs engineered with these ZFA-precursors--with further optimization to enhance their specificity to only darc and glycophorin-a, could be used in constructing an experimental gene-based-malaria vaccine. Alternatively, meganucleases and transcription activator-like (TAL) nucleases that target conserved stretches of darc and glycophorin-a DNA may serve the purpose of abrogating invasion of RBCs by falciparam and vivax plasmodia species.

PMID:
22938508
[PubMed]
PMCID:
PMC3500210
Free PMC Article
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