Disease Progression in Plasmodium knowlesi Malaria Is Linked to Variation in Invasion Gene Family Members
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 parasi...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
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Public Library of Science
2014
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| Online Access: | http://ir.unimas.my/id/eprint/7391/ |
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| author | Atique M, Ahmed Miguel M, Pinheiro Paul C, Divis Angela, Siner Ramlah, Zainudin Tien, Wong Chan, Woon Lu Sarina K, Singh-Khaira Scott B, Millar Sean, Lynch Matthias, Willmann Balbir, Singh Sanjeev, Krishna Janet, Cox-Singh |
| author_facet | Atique M, Ahmed Miguel M, Pinheiro Paul C, Divis Angela, Siner Ramlah, Zainudin Tien, Wong Chan, Woon Lu Sarina K, Singh-Khaira Scott B, Millar Sean, Lynch Matthias, Willmann Balbir, Singh Sanjeev, Krishna Janet, Cox-Singh |
| author_sort | Atique M, Ahmed |
| building | UNIMAS Institutional Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-15T06:18:41Z |
| format | Article |
| id | unimas-7391 |
| institution | Universiti Malaysia Sarawak |
| institution_category | Local University |
| last_indexed | 2025-11-15T06:18:41Z |
| publishDate | 2014 |
| publisher | Public Library of Science |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | unimas-73912017-02-24T07:25:14Z http://ir.unimas.my/id/eprint/7391/ Disease Progression in Plasmodium knowlesi Malaria Is Linked to Variation in Invasion Gene Family Members Atique M, Ahmed Miguel M, Pinheiro Paul C, Divis Angela, Siner Ramlah, Zainudin Tien, Wong Chan, Woon Lu Sarina K, Singh-Khaira Scott B, Millar Sean, Lynch Matthias, Willmann Balbir, Singh Sanjeev, Krishna Janet, Cox-Singh Q Science (General) QH301 Biology 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. Public Library of Science 2014-08-14 Article PeerReviewed Atique M, Ahmed and Miguel M, Pinheiro and Paul C, Divis and Angela, Siner and Ramlah, Zainudin and Tien, Wong and Chan, Woon Lu and Sarina K, Singh-Khaira and Scott B, Millar and Sean, Lynch and Matthias, Willmann and Balbir, Singh and Sanjeev, Krishna and Janet, Cox-Singh (2014) Disease Progression in Plasmodium knowlesi Malaria Is Linked to Variation in Invasion Gene Family Members. PLoS neglected tropical diseases, 8 (8). e3086. ISSN 1935-2735 http://dx.plos.org/10.1371/journal.pntd.0003086 DOI: 10.1371/journal.pntd.0003086 |
| spellingShingle | Q Science (General) QH301 Biology Atique M, Ahmed Miguel M, Pinheiro Paul C, Divis Angela, Siner Ramlah, Zainudin Tien, Wong Chan, Woon Lu Sarina K, Singh-Khaira Scott B, Millar Sean, Lynch Matthias, Willmann Balbir, Singh Sanjeev, Krishna Janet, Cox-Singh Disease Progression in Plasmodium knowlesi Malaria Is Linked to Variation in Invasion Gene Family Members |
| title | Disease Progression in Plasmodium knowlesi Malaria Is Linked to Variation in Invasion Gene Family Members |
| title_full | Disease Progression in Plasmodium knowlesi Malaria Is Linked to Variation in Invasion Gene Family Members |
| title_fullStr | Disease Progression in Plasmodium knowlesi Malaria Is Linked to Variation in Invasion Gene Family Members |
| title_full_unstemmed | Disease Progression in Plasmodium knowlesi Malaria Is Linked to Variation in Invasion Gene Family Members |
| title_short | Disease Progression in Plasmodium knowlesi Malaria Is Linked to Variation in Invasion Gene Family Members |
| title_sort | disease progression in plasmodium knowlesi malaria is linked to variation in invasion gene family members |
| topic | Q Science (General) QH301 Biology |
| url | http://ir.unimas.my/id/eprint/7391/ http://ir.unimas.my/id/eprint/7391/ http://ir.unimas.my/id/eprint/7391/ |