Quantifying the removal of red blood cells in Macaca mulatta during a Plasmodium coatneyi infection

• Authors: Luis L. Fonseca, Georgia Institute of Technology; Harnel S. Alezi, Georgia Institute of Technology; C. Moreno, Emory University; John W. Barnwell, Centers for Disease Control and Prevention; Mary Galinski, Emory University; Eberhard Voit, Emory University
• Journal Title: Malaria Journal
• Volume: Volume 15, Number 1
• Publisher: BioMed Central | 2016-08-12, Pages 410-410
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1186/s12936-016-1465-5
• Subjects: Health Sciences, Pathology; Health Sciences, Epidemiology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Infectious Diseases; Parasitology; Tropical Medicine; Macaca mulatta; Malarial anaemia; Mathematical model; Plasmodium coatneyi; Red blood cell removal; OCCURRING ANTI-BAND-3 ANTIBODIES; SEVERE MALARIAL ANEMIA; FALCIPARUM-MALARIA; UNINFECTED ERYTHROCYTES; HEMOGLOBIN; ERYTHROPOIESIS; BAND-3; SENESCENCE; KNOWLESI; DISEASE

Abstract

BACKGROUND: Malaria is the most deadly parasitic disease in humans globally, and the long-time coexistence with malaria has left indelible marks in the human genome that are the causes of a variety of genetic disorders. Although anaemia is a common clinical complication of malaria, the root causes and mechanisms involved in the pathogenesis of malarial anaemia are unclear and difficult to study in humans. Non-human primate (NHP) model systems enable the mechanistic study and quantification of underlying causative factors of malarial anaemia, and particularly the onset of severe anaemia. METHODS: Data were obtained in the course of Plasmodium coatneyi infections of malaria-naïve and semi-immune rhesus macaques (Macaca mulatta), whose red blood cells (RBCs) were labelled in situ with biotin at the time the infections were initiated. The data were used for a survival analysis that permitted, for the first time, an accurate estimation of the lifespan of erythrocytes in macaques. The data furthermore formed the basis for the development and parameterization of a recursive dynamic model of erythrocyte turnover, which was used for the quantification of RBC production and removal in each macaque. RESULTS: The computational analysis demonstrated that the lifespan of erythrocytes in macaques is 98 ± 21 days. The model also unambiguously showed that death due to senescence and parasitaemia is not sufficient to account for the extent of infection-induced anaemia. Specifically, the model permits, for the first time, the quantification of the different causes of RBC death, namely, normal senescence, age-independent random loss, parasitization, and bystander effects in uninfected cells. Such a dissection of the overall RBC removal process is hardly possible with experimental means alone. In the infected malaria-naïve macaques, death of erythrocytes by normal physiological senescence processes accounts for 20 % and parasitization for only 4 %, whereas bystander effects are associated with an astonishing 76 % of total RBC losses. Model-based comparisons of alternative mechanisms involved in the bystander effect revealed that most of the losses are likely due to a process of removing uninfected RBCs of all age classes and only minimally due to an increased rate of senescence of the uninfected RBCs. CONCLUSIONS: A new malaria blood-stage model was developed for the analysis of data characterizing P. coatneyi infections of M. mulatta. The model used a discrete and recursive framework with age-structure that allowed the quantification of the most significant pathophysiological processes of RBC removal. The computational results revealed that the malarial anaemia caused by this parasite is mostly due to a loss of uninfected RBCs by an age-independent process. The biological identity and complete mechanism of this process is not fully understood and requires further investigation.