Abstract
BackgroundPlasmodium vivax can cause severe malaria. The total parasite biomass during infections is correlated with the severity of disease but not necessarily quantified accurately by microscopy. This finding has raised the question whether there could be sub-populations of parasites that are not observed in peripheral blood smears but continue to contribute to the increase in parasite numbers that drive pathogenesis. Non-human primate infection models utilizing the closely related simian malaria parasite Plasmodium cynomolgi hold the potential for quantifying the magnitude of possibly unobserved infected red blood cell (iRBC) populations and determining how the presence of this hidden reservoir correlates with disease severity.MethodsTime series data tracking the longitudinal development of parasitaemia in five Macaca mulatta infected with P. cynomolgi were used to design a computational model quantifying iRBCs that circulate in the blood versus those that are not detectable and are termed here as ‘concealed’. This terminology is proposed to distinguish such observations from the deep vascular and widespread ‘sequestration’ of Plasmodium falciparum iRBCs, which is governed by distinctly different molecular mechanisms.ResultsThe computational model presented here clearly demonstrates that the observed growth data of iRBC populations are not consistent with the known biology and blood-stage cycle of P. cynomolgi. However, the discrepancies can be resolved when a sub-population of concealed iRBCs is taken into account. The model suggests that the early growth of a hidden parasite sub-population has the potential to drive disease. As an alternative, the data could be explained by the sequential release of merozoites from the liver over a number of days, but this scenario seems less likely.ConclusionsConcealment of a non-circulating iRBC sub-population during P. cynomolgi infection of M. mulatta is an important aspect of this successful host–pathogen relationship. The data also support the likelihood that a sub-population of iRBCs of P. vivax has a comparable means to become withdrawn from the peripheral circulation. This inference has implications for understanding vivax biology and pathogenesis and stresses the importance of considering a concealed parasite reservoir with regard to vivax epidemiology and the quantification and treatment of P. vivax infections.
Highlights
10,000, 20,000 or 30,000 merozoites are used in these simulations does not affect the locations of the dots much, as the results are exhibited on a log-10 scale. Until this Century, it was generally thought that P. falciparum was the only human malaria parasite able to ‘hide’ its maturing asexual stage infected red blood cell (iRBC), presumably to prevent removal by the spleen, and through processes that have come to be known as cytoadherence and sequestration
The model presented here may be a useful tool in the future to aid the quantification of the infected cell populations in non-human primate (NHP) infection studies that can combine carefully timed blood and bone marrow draws, as well as necropsies, and to identify the potential tissues in which the parasites may preferentially be concealed and make quantitative assessments of the parasite load vis-àvis pathology
In 1991, Fremount and Rossan [67] found that the presence of P. vivax iRBCs was five to ten times greater in a juvenile marmoset compared to an adult, and that they predominated in liver, spleen and lung
Summary
Non-human primate infection models utilizing the closely related simian malaria parasite Plasmodium cynomolgi hold the potential for quantifying the magnitude of possibly unobserved infected red blood cell (iRBC) populations and determining how the presence of this hidden reservoir correlates with disease severity. Plasmodium vivax is a major infectious disease agent that causes substantial morbidity in communities around the world where it is endemic, and about 2.5 billion people live at risk of infection and possible death [1,2,3] Most critically, this species has a dormant stage in the liver that can activate and cause new blood infections known as relapse infections (reviewed in [4,5,6]). The mechanisms of infected red blood cell (iRBC) biology of these two Plasmodium species, host-parasite interactions, possible adhesion and resulting pathology remain largely unexplored
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