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Author Notes:

Luis L. Fonseca, Email: llfonseca@gatech.edu

Conceived and designed the model: LLF and EOV.

Performed simulations and optimizations: LLF.

Managed and deposited the data and metadata: members of the MaHPIC consortium.

Performed data analysis: LLF, CJJ.

Generated the figures: LLF, CJJ.

Interpreted the results: LLF, EOV, AM, CJJ, MRG, and JWB.

Wrote the paper: LLF and EOV.

Executed validations experiments and analysis: CS and CJJ.

Provided expert knowledge, viewpoints and manuscript contributions: MRG, AM, JWB and members of the MaHPIC consortium.

All authors read and approved the final manuscript.

The authors would like to thank Anuj Gupta, James Wade, and Nathan Chiappa for fruitful discussions.

The authors would also like to thank Daniel Olivença for proof-reading the methods section and for all the discussions.

The authors declare that they have no competing interests.

Subjects:

Research Funding:

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:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Infectious Diseases
  • Parasitology
  • Tropical Medicine
  • Mathematical model
  • Host-pathogen interactions
  • Macaca mulatta
  • Plasmodium cynomolgi
  • Plasmodium vivax
  • Reticulocytes
  • Anaemia
  • Zoonosis
  • RED-BLOOD-CELLS
  • CAVEOLA-VESICLE COMPLEXES
  • ACUTE MALARIA INFECTIONS
  • LIVER-STAGE
  • FALCIPARUM-MALARIA
  • SCHUFFNERS DOTS
  • VIVAX
  • ANEMIA
  • PARASITES
  • RETICULOCYTES

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

Tools:

Journal Title:

Malaria Journal

Volume:

Volume 17, Number 1

Publisher:

, Pages 410-410

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2018 The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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