Abstract
Infection with Plasmodium knowlesi, a zoonotic primate malaria, is a growing human health problem in Southeast Asia. P. knowlesi is being used in malaria vaccine studies, and a number of proteins are being considered as candidate malaria vaccine antigens, including the Apical Membrane Antigen 1 (AMA1). In order to determine genetic diversity of the ama1 gene and to identify epitopes of AMA1 under strongest immune selection, the ama1 gene of 52 P. knowlesi isolates derived from human infections was sequenced. Sequence analysis of isolates from two geographically isolated regions in Sarawak showed that polymorphism in the protein is low compared to that of AMA1 of the major human malaria parasites, P. falciparum and P. vivax. Although the number of haplotypes was 27, the frequency of mutations at the majority of the polymorphic positions was low, and only six positions had a variance frequency higher than 10%. Only two positions had more than one alternative amino acid. Interestingly, three of the high-frequency polymorphic sites correspond to invariant sites in PfAMA1 or PvAMA1. Statistically significant differences in the quantity of three of the six high frequency mutations were observed between the two regions. These analyses suggest that the pkama1 gene is not under balancing selection, as observed for pfama1 and pvama1, and that the PkAMA1 protein is not a primary target for protective humoral immune responses in their reservoir macaque hosts, unlike PfAMA1 and PvAMA1 in humans. The low level of polymorphism justifies the development of a single allele PkAMA1-based vaccine.
Highlights
In the last decade it has become increasingly clear that the simian malaria parasite, Plasmodium knowlesi, is widely distributed in Southeast Asia and can cause severe disease and death in humans [1,2]
Analysis of the translations of the 52 pkama1 gene sequences showed that the overall amino acid polymorphism of P. knowlesi AMA1 (PkAMA1) is low compared to that of PfAMA1
The frequency of the occurrence of alternative amino acids in the PkAMA1 sequences was low, as this frequency was higher than 10% at six amino acid positions only, while single mutations were found at 10 amino acids positions
Summary
In the last decade it has become increasingly clear that the simian malaria parasite, Plasmodium knowlesi, is widely distributed in Southeast Asia and can cause severe disease and death in humans [1,2]. Its distribution coincides largely with the distribution of its natural hosts, the longtailed and pig-tailed macaques, and the Anopheline vectors belonging to the Anopheles leucosphyrus group [1]. P. knowlesi infections in humans were overlooked for a long time as they were misdiagnosed by microscopy as the morphologically similar P. malariae [2]. P. knowlesi is considered a serious threat, responsible for approximately 66% of all hospitalized malaria cases for the year 2013 in Malaysian Borneo [3]. P. knowlesi is an ancient parasite that has been infecting humans for a long time [4], such infections are considered to be primarily a zoonotic event. There are no biological barriers that would prevent transmission by mosquitoes from macaques to humans and from humans to humans, and this has been demonstrated under laboratory conditions [5]
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