A model of Plasmodium vivax concealment based on Plasmodium cynomolgi infections in Macaca mulatta

• Type of Material: Article
• Authors: Luis L. Fonseca, Georgia Institute of Technology; Chester J. Joyner, Emory University; Mary Galinski, Emory University; Eberhard Voit, Emory University
• Language: English
• Date: 2017-09-18
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12936-017-2008-4
• Title of Journal or Parent Work: Malaria Journal
• ISSN: 1475-2875
• Volume: 16
• Start Page: 375
• End Page: 375
• Grant/Funding Information: This project was funded in part by federal funds from the US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under contract # HHSN272201200031C (PI: MRG), which supports the Malaria Host–Pathogen Interaction Center (MaHPIC), as well as the Office of Research Infrastructure Programs/OD P51OD011132.
• Keywords: Systems biology; Parasite dynamics; Malaria; Host–pathogen interactions; Sequestration; Plasmodium falciparum; Mathematical model
• Research Categories: Engineering, Biomedical; Biology, Microbiology; Biology, Virology

Abstract

Background: Plasmodium 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. Methods: Time 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. Results: The 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. Conclusions: Concealment 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.