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Disease progression in Plasmodium knowlesi malaria is linked to variation in invasion gene family members.

Ahmed, AM; Pinheiro, MM; Divis, PC; Siner, A; Zainudin, R; Wong, IT; Lu, CW; Singh-Khaira, SK; Millar, SB; Lynch, S; et al. Ahmed, AM; Pinheiro, MM; Divis, PC; Siner, A; Zainudin, R; Wong, IT; Lu, CW; Singh-Khaira, SK; Millar, SB; Lynch, S; Willmann, M; Singh, B; Krishna, S; Cox-Singh, J (2014) Disease progression in Plasmodium knowlesi malaria is linked to variation in invasion gene family members. PLoS Neglected Tropical Diseases, 8 (8). ISSN 1935-2735 https://doi.org/10.1371/journal.pntd.0003086
SGUL Authors: Krishna, Sanjeev

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Abstract

Emerging pathogens undermine initiatives to control the global health impact of infectious diseases. Zoonotic malaria is no exception. Plasmodium knowlesi, a malaria parasite of Southeast Asian macaques, has entered the human population. P. knowlesi, like Plasmodium falciparum, can reach high parasitaemia in human infections, and the World Health Organization guidelines for severe malaria list hyperparasitaemia among the measures of severe malaria in both infections. Not all patients with P. knowlesi infections develop hyperparasitaemia, and it is important to determine why. Between isolate variability in erythrocyte invasion, efficiency seems key. Here we investigate the idea that particular alleles of two P. knowlesi erythrocyte invasion genes, P. knowlesi normocyte binding protein Pknbpxa and Pknbpxb, influence parasitaemia and human disease progression. Pknbpxa and Pknbpxb reference DNA sequences were generated from five geographically and temporally distinct P. knowlesi patient isolates. Polymorphic regions of each gene (approximately 800 bp) were identified by haplotyping 147 patient isolates at each locus. Parasitaemia in the study cohort was associated with markers of disease severity including liver and renal dysfunction, haemoglobin, platelets and lactate, (r = ≥ 0.34, p =  <0.0001 for all). Seventy-five and 51 Pknbpxa and Pknbpxb haplotypes were resolved in 138 (94%) and 134 (92%) patient isolates respectively. The haplotypes formed twelve Pknbpxa and two Pknbpxb allelic groups. Patients infected with parasites with particular Pknbpxa and Pknbpxb alleles within the groups had significantly higher parasitaemia and other markers of disease severity. Our study strongly suggests that P. knowlesi invasion gene variants contribute to parasite virulence. We focused on two invasion genes, and we anticipate that additional virulent loci will be identified in pathogen genome-wide studies. The multiple sustained entries of this diverse pathogen into the human population must give cause for concern to malaria elimination strategists in the Southeast Asian region.

Item Type: Article
Additional Information: © 2014 Ahmed et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Tropical Medicine, 06 Biological Sciences, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: PLoS Neglected Tropical Diseases
Article Number: e3086
ISSN: 1935-2735
Language: eng
Dates:
DateEvent
14 August 2014Published
Projects:
Project IDFunderFunder ID
G0801971Medical Research CouncilUNSPECIFIED
ISSF 097831/Z/11/ZWellcome TrustUNSPECIFIED
PubMed ID: 25121807
Go to PubMed abstract
URI: http://sgultest.da.ulcc.ac.uk/id/eprint/107349
Publisher's version: https://doi.org/10.1371/journal.pntd.0003086

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