Analysis of erythrocyte dynamics in Rhesus macaque monkeys during infection with Plasmodium cynomolgi

• Type of Material: Article
• Authors: Luis L. Fonseca, Georgia Institute of Technology; Chester J. Joyner, Emory University; Celia L. Saney, Emory University; Alberto Moreno, Emory University; John W. Barnwell, Emory University; Mary Galinski, Emory University; Eberhard Voit, Emory University
• Language: English
• Date: 2018-11-06
• Publisher: BMC (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12936-018-2560-6
• Title of Journal or Parent Work: Malaria Journal
• ISSN: 1475-2875
• Volume: 17
• Issue: 1
• Start Page: 410
• End Page: 410
• 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: Mary R. Galinski), which supports the Malaria Host–Pathogen Interaction Center (MaHPIC), as well as the Office of Research Infrastructure Programs/OD P51OD011132 (formerly National Center for Research Resources P51RR000165).
• Keywords: Zoonosis; VIVAX; LIVER-STAGE; Plasmodium vivax; Macaca mulatta; Science & Technology; ACUTE MALARIA INFECTIONS; Infectious Diseases; RETICULOCYTES; RED-BLOOD-CELLS; Life Sciences & Biomedicine; CAVEOLA-VESICLE COMPLEXES; SCHUFFNERS DOTS; ANEMIA; PARASITES; Plasmodium cynomolgi; Parasitology; Host-pathogen interactions; Reticulocytes; Tropical Medicine; Mathematical model; FALCIPARUM-MALARIA; Anaemia
• Research Categories: Engineering, Biomedical; Health Sciences, Immunology

Abstract

Background: Malaria is a major mosquito transmitted, blood-borne parasitic disease that afflicts humans. The disease causes anaemia and other clinical complications, which can lead to death. Plasmodium vivax is known for its reticulocyte host cell specificity, but many gaps in disease details remain. Much less is known about the closely related species, Plasmodium cynomolgi, although it is naturally acquired and causes zoonotic malaria. Here, a computational model is developed based on longitudinal analyses of P. cynomolgi infections in nonhuman primates to investigate the erythrocyte dynamics that is pertinent to understanding both P. cynomolgi and P. vivax malaria in humans. Methods: A cohort of five P. cynomolgi infected Rhesus macaques (Macaca mulatta) is studied, with individuals exhibiting a plethora of clinical outcomes, including varying levels of anaemia. A discrete recursive model with age structure is developed to replicate the dynamics of P. cynomolgi blood-stage infections. The model allows for parasitic reticulocyte preference and assumes an age preference among the mature RBCs. RBC senescence is modelled using a hazard function, according to which RBCs have a mean lifespan of 98 ± 21 days. Results: Based on in vivo data from three cohorts of macaques, the computational model is used to characterize the reticulocyte lifespan in circulation as 24 ± 5 h (n = 15) and the rate of RBC production as 2727 ± 209 cells/h/μL (n = 15). Analysis of the host responses reveals a pre-patency increase in the number of reticulocytes. It also allows the quantification of RBC removal through the bystander effect. Conclusions: The evident pre-patency increase in reticulocytes is due to a shift towards the release of younger reticulocytes, which could result from a parasite-induced factor meant to increase reticulocyte availability and satisfy the parasite's tropism, which has an average value of 32:1 in this cohort. The number of RBCs lost due to the bystander effect relative to infection-induced RBC losses is 62% for P. cynomolgi infections, which is substantially lower than the value of 95% previously determined for another simian species, Plasmodium coatneyi.