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

Ahmed, A. M. et al. (2014) Disease progression in Plasmodium knowlesi malaria is linked to variation in invasion gene family members. PLoS Neglected Tropical Diseases, 8(8), e3086. (doi: 10.1371/journal.pntd.0003086) (PMID:25121807) (PMCID:PMC4133233)

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: Articles
• Additional Information: This study was funded by The Medical Research Council (MRC) UK; Grant number G0801971, http://www.mrc.ac.uk. MMP is supported by The Wellcome Trust (ISSF 097831/Z/11/Z), http://www.wellcome.ac.uk.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Millar, Mr Scott
• Authors: Ahmed, A. M., Pinheiro, M. M., Divis, P. C., Siner, A., Zainudin, R., Wong, I. T., Lu, C. W., Singh-Khaira, S. K., Millar, S. B., Lynch, S., Willmann, M., Singh, B., Krishna, S., and Cox-Singh, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: PLoS Neglected Tropical Diseases
• Publisher: Public Library of Science
• ISSN: 1935-2727
• ISSN (Online): 1935-2735
• Published Online: 14 August 2014
• Copyright Holders: Copyright © 2014 Ahmed et al.
• First Published: First published in PLoS Neglected Tropical Diseases 8(8): e3086
• Publisher Policy: Reproduced under a Creative Commons License