Population dynamics of untreated <i>Plasmodium falciparum</i> malaria within the adult human host during the expansion phase of the infection

Simpson, Julie A; Aarons, Leon; Collins, William E.; Jeffery, Geoffrey M.; White, Nicholas J.

doi:10.1017/s0031182001001202

Cited by 123 publications

(129 citation statements)

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“…It is further assumed that the test set, y, is at some stage, t*, in the HPI such that y g ϭ xg(t*) ϩ g where g Ϸ N(0, 2 ). The assumption of Gaussian noise closely conforms to previous biological findings (26), with 2 estimated, using differences across the 3 clones measured by Lliná s et al (7).…”

Section: Microscopysupporting

confidence: 83%

Statistical estimation of cell-cycle progression and lineage commitment in Plasmodium falciparum reveals a homogeneous pattern of transcription in ex vivo culture

Lemieux

Gomez-Escobar

Feller

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

129

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We have cultured Plasmodium falciparum directly from the blood of infected individuals to examine patterns of mature-stage gene expression in patient isolates. Analysis of the transcriptome of P. falciparum is complicated by the highly periodic nature of gene expression because small variations in the stage of parasite development between samples can lead to an apparent difference in gene expression values. To address this issue, we have developed statistical likelihood-based methods to estimate cell cycle progression and commitment to asexual or sexual development lineages in our samples based on microscopy and gene expression patterns. In cases subsequently matched for temporal development, we find that transcriptional patterns in ex vivo culture display little variation across patients with diverse clinical profiles and closely resemble transcriptional profiles that occur in vitro. These statistical methods, available to the research community, assist in the design and interpretation of P. falciparum expression profiling experiments where it is difficult to separate true differential expression from cell-cycle dependent expression. We reanalyze an existing dataset of in vivo patient expression profiles and conclude that previously observed discrete variation is consistent with the commitment of a varying proportion of the parasite population to the sexual development lineage. malaria ͉ microarray

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Section: Microscopysupporting

confidence: 83%

Statistical estimation of cell-cycle progression and lineage commitment in Plasmodium falciparum reveals a homogeneous pattern of transcription in ex vivo culture

Lemieux

Gomez-Escobar

Feller

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

129

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“…The best source of in vivo data in humans comes from the treatment of patients with neurosyphilis by infection with malaria. Between-strain variation in parasite growth rate and virulence has been demonstrated in these data from P. falciparum ( James et al 1932;Jeffery & Eyles 1955;Gravenor et al 1995;Simpson et al 2002;Read et al 2003) as have differences in infection length (Jeffery & Eyles 1954, 1955, infectivity to mosquitoes ( Jeffery & Eyles 1955) and gametocyte circulation time . Variation in asexual growth rate in vitro of wild-caught P. falciparum isolates exists and, importantly, this correlates positively to in vivo virulence (Chotivanich et al 2000).…”

Section: Virulence-transmissibility Relationships In Plasmodium Falcimentioning

confidence: 85%

Virulence in malaria: an evolutionary viewpoint

Mackinnon

Read

2004

Phil. Trans. R. Soc. Lond. B

225

204

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Malaria parasites cause much morbidity and mortality to their human hosts. From our evolutionary perspective, this is because virulence is positively associated with parasite transmission rate. Natural selection therefore drives virulence upwards, but only to the point where the cost to transmission caused by host death begins to outweigh the transmission benefits. In this review, we summarize data from the laboratory rodent malaria model, Plasmodium chabaudi, and field data on the human malaria parasite, P. falciparum, in relation to this virulence trade-off hypothesis. The data from both species show strong positive correlations between asexual multiplication, transmission rate, infection length, morbidity and mortality, and therefore support the underlying assumptions of the hypothesis. Moreover, the P. falciparum data show that expected total lifetime transmission of the parasite is maximized in young children in whom the fitness cost of host mortality balances the fitness benefits of higher transmission rates and slower clearance rates, thus exhibiting the hypothesized virulence trade-off. This evolutionary explanation of virulence appears to accord well with the clinical and molecular explanations of pathogenesis that involve cytoadherence, red cell invasion and immune evasion, although direct evidence of the fitness advantages of these mechanisms is scarce. One implication of this evolutionary view of virulence is that parasite populations are expected to evolve new levels of virulence in response to medical interventions such as vaccines and drugs.

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“…Third, RBCs infected with the virulent clone may release a larger number of merozoites into the bloodstream. Given that these maximum growth rates are observed in the initial stages of infection when anaemia and immune regulation are less influential, we consider the third explanation to be the most likely (see Simpson et al 2002). If regulation was entirely top-down, then our model predicts that the virulent clone should release ca.…”

Section: Discussionmentioning

confidence: 98%

Topndash;down or bottom–up regulation of intra–host blood–stage malaria: do malaria parasites most resemble the dynamics of prey or predator?

Haydon¹,

Matthews²,

Timms

et al. 2003

Proc. R. Soc. Lond. B

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Knowledge of the factors that limit parasite numbers offers hope of improved intervention strategies as well as exposing the selective forces that have shaped parasite life-history strategies. We develop a theoretical framework with which to consider the intra-host regulation of malaria parasite density. We analyse a general model that relates timing and magnitude of peak parasite density to initial dose under three different regulatory processes. The dynamics can be regulated either by top-down processes (upgradable immune regulation), bottom-up processes (fixed immune response and red blood cell (RBC) limitation) or a mixture of the two. We define and estimate the following key parameters: (i) the rate of RBC replenishment; (ii) the rate of destruction of uninfected RBCs; and (iii) the maximum parasite growth rate.Comparing predictions of this model with experimental results for rodent malaria in laboratory mice allowed us to reject functional forms of immune upregulation and/or effects of RBC limitation that were inconsistent with the data. Bottom-up regulation alone was insufficient to account for observed patterns without invoking either localized depletion of RBC density or merozoite interference. By contrast, an immune function upregulated in proportion to either merozoite or infected RBC density was consistent with observed dynamics. An immune response directed solely at merozoites required twice the level of activation of one directed at infected RBCs.

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Population dynamics of untreated Plasmodium falciparum malaria within the adult human host during the expansion phase of the infection

Cited by 123 publications

References 0 publications

Statistical estimation of cell-cycle progression and lineage commitment in Plasmodium falciparum reveals a homogeneous pattern of transcription in ex vivo culture

Statistical estimation of cell-cycle progression and lineage commitment in Plasmodium falciparum reveals a homogeneous pattern of transcription in ex vivo culture

Virulence in malaria: an evolutionary viewpoint

Topndash;down or bottom–up regulation of intra–host blood–stage malaria: do malaria parasites most resemble the dynamics of prey or predator?

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