PNAS AND SCIENTIFIC REPORTS PUBLICATION RESULTING FROM PLASMODIUM KNOWLESI STUDY
HIR congratulates Associate Professor Dr. Lau Yee Ling and Dr. Amirah Amir, Department of Parasitology, and their research team for the twin publications arising from their HIR funded malaria project in Nature Scientific Reports and Proceedings of the National Academy of Sciences (PNAS).
Plasmodium knowlesi is a zoonotic parasite of cynomologus macaque monkeys found throughout South East Asia, particularly in Malaysia, Borneo, Thailand, Myanmar, Philippines and Singapore. Humans who work at the forest fringe or enter the rainforest to work are at high risk of infection. It has become the dominant strain as the cause of malaria in Malaysia, having overtaken P. vivax. In 2014, knowlesi malaria accounted for 38% of reported malaria cases in Malaysia, thus making its study of public health importance.
Invasion characteristics of a Plasmodium knowlesi line newly isolated from a human.
Amirah Amir, Bruce Russell, Jonathan Wee Kent Liew, Robert W. Moon, Mun Yik Fong, Indra Vythilingam, Vellayan Subramaniam, Georges Snounou, Yee Ling Lau (2016). Nature Scientific Reports (DOI: 10.1038/srep24623).
The study of the biology of malaria parasite was primarily based on using P. knowlesi strains that have been passaged through a multitude of animals over the last 50 to 80 years. Such long periods of propagation in cells from the non-natural hosts might have altered the characteristics of the parasite. Realizing that this may significantly limit our understanding of the contemporary populations of P. knowlesi that threaten human health today, we isolated a new line of P. knowlesi from a human, named UM01 and compared some of its invasive characteristics to those of one of the H strain’s cloned lines (A1-H.1) that were adapted to human red blood cells (RBCs).
In this Nature Scientific Reports article, the UM01 and A1-H.1 lines were found to readily invade human and macaque (Macaca fascicularis) normocytes with a preference for reticulocytes. Whereas invasion of human RBCs was dependent on the presence of the Duffy antigen/receptor for chemokines (DARC) for both parasite lines, this was not the case for macaque RBCs. The duration of the erythrocytic cycle for the cloned UM01 line was consistently shorter than that of the A1-H.1 line and gametocyte production appeared to be impaired in the latter. These preliminary observations might indicate the potential phenotypic diversity of P. knowlesi parasites.
Normocyte binding protein required for human erythrocyte invasion by the zoonotic malaria parasite Plasmodium knowlesi.
Robert W. Moon, Hazem Sharaf, Claire H. Hastings, Yung Shwen Ho, Mridul B. Nair, Zineb Rchiad, Ellen Knuepfer, Abhinay Ramaprasad, Franziska Mohring, Amirah Amir, Noor A. Yusuf, Joanna Hall, Neil Almond, Yee Ling Lau, Arnab Pain, Michael J. Blackman and Anthony A. Holder (2016). PNAS (Proceedings of the National Academy of Sciences of the United States of America).
In collaboration with The London School of Infectious and Tropical Diseases, The Francis Crick Institute, London and other international institutions, we embarked on a study to comparatively analyse the genomes of P. knowlesi lines adapted to human or cynomolgus RBCs in culture, in parallel with that of the pre-adapted parasites. This study came about following the observation that whilst P. knowlesi can be readily grown in both cynomolgus and rhesus macaque RBCs in vitro, it requires extended adaptation for growth in human RBCs in vitro displaying insufficient invasion efficiency in human RBCs to support continuous culture. Previous work overcame this impediment by extended adaptation in a mixture of human and cynomolgus RBCs, producing a parasite line that can be maintained in human RBCs alone which suggested that improved parasite invasion of human RBCs was essential for maintenance of parasite growth in vitro.
In this PNAS article, culture adaptation of P. knowlesi was found to be associated with distinct large genomic deletions and duplications, including the loss of NBPXa (normocyte binding protein Xa) in parasites adapted to growth in cynomolgus RBCs. Following this, the researchers also found NBPXa to be unnecessary for invasion of cynomolgus RBCs but crucial for invasion of human RBCs. NBPXa was identified and proven to be a key mediator of P. knowlesi human infection which makes it a potential target for inclusion in vaccines to prevent human infection.
Assoc. Prof. Dr. Lau Yee Ling & Dr. Amirah
Giemsa stained smear of P. knowlesi (UM01line) showing a gametocyte
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