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Where have all the parasites gone? Modelling early malaria parasite sequestration dynamics.

ABSTRACT: Traditional approaches to measuring the level of malaria infection involve counting the proportion of parasite-infected red blood cells (iRBC) in circulating blood, known as parasitaemia. However, iRBC can also accumulate within the microvasculature of tissues and organs, a process called sequestration. Thus measurements of parasitemia do not necessarily reflect the total parasite burden (TPB). Recent experimental advances have allowed TPB measurements to be made in humans and experimental models. TPB is particularly important because it is the best current predictor of malaria disease severity and death in humans. Understanding the relationship between freely circulating iRBC versus tissue-sequestered iRBC is an important question in infection dynamics. The recent ability to experimentally measure the dynamics of iRBC in blood and tissue during murine malaria provides an exciting potential window into sequestration, but new modeling approaches are clearly required to understand these interactions. We present a model of malaria dynamics during early infection that incorporates iRBC that both circulate in the blood and sequester in tissue microvasculature. We explore the effect that perturbations to the system have on the ratio of the number of iRBC between these compartments, and consider which changes are most consistent with experimental data from mice. Using this model we predict an increase in the clearance rate of sequestered iRBCs around the time when mild symptoms become apparent, but a more pronounced increase in the rate of sequestration of iRBCs associated with the onset of severe malaria symptoms.

SUBMITTER: Cromer D

PROVIDER: S-EPMC3575381 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Where have all the parasites gone? Modelling early malaria parasite sequestration dynamics.

Cromer Deborah D Best Shannon E SE Engwerda Christian C Haque Ashraful A Davenport Miles M

PloS one 20130218 2

Traditional approaches to measuring the level of malaria infection involve counting the proportion of parasite-infected red blood cells (iRBC) in circulating blood, known as parasitaemia. However, iRBC can also accumulate within the microvasculature of tissues and organs, a process called sequestration. Thus measurements of parasitemia do not necessarily reflect the total parasite burden (TPB). Recent experimental advances have allowed TPB measurements to be made in humans and experimental model ...[more]

PMID: 23441158

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Project description:During intra-erythrocytic development, late asexually replicating Plasmodium falciparum parasites sequester from peripheral circulation. This facilitates chronic infection and is linked to severe disease and organ-specific pathology including cerebral and placental malaria. Immature gametocytes - sexual stage precursor cells - likewise disappear from circulation. Recent work has demonstrated that these sexual stage parasites are located in the hematopoietic system of the bone marrow before mature gametocytes are released into the bloodstream to facilitate mosquito transmission. However, as sequestration occurs only in vivo and not during in vitro culture, the mechanisms by which it is regulated and enacted (particularly by the gametocyte stage) remain poorly understood.We generated the most comprehensive P. falciparum functional gene network to date by integrating global transcriptional data from a large set of asexual and sexual in vitro samples, patient-derived in vivo samples, and a new set of in vitro samples profiling sexual commitment. We defined more than 250 functional modules (clusters) of genes that are co-expressed primarily during the intra-erythrocytic parasite cycle, including 35 during sexual commitment and gametocyte development. Comparing the in vivo and in vitro datasets allowed us, for the first time, to map the time point of asexual parasite sequestration in patients to 22 hours post-invasion, confirming previous in vitro observations on the dynamics of host cell modification and cytoadherence. Moreover, we were able to define the properties of gametocyte sequestration, demonstrating the presence of two circulating gametocyte populations: gametocyte rings between 0 and approximately 30 hours post-invasion and mature gametocytes after around 7 days post-invasion.This study provides a bioinformatics resource for the functional elucidation of parasite life cycle dynamics and specifically demonstrates the presence of the gametocyte ring stages in circulation, adding significantly to our understanding of the dynamics of gametocyte sequestration in vivo.

Dataset Information

Where have all the parasites gone? Modelling early malaria parasite sequestration dynamics.

Publications

Where have all the parasites gone? Modelling early malaria parasite sequestration dynamics.

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