Plasmodium falciparum parasitaemia described by a new mathematical model

Department of Medical Biometry, University of Tübingen, Germany.
Parasitology (Impact Factor: 2.56). 05/2001; 122(Pt 4):379-91. DOI: 10.1017/S0031182001007533
Source: PubMed


A new mathematical model of Plasmodium falciparum asexual parasitaemia is formulated and fitted to 35 malaria therapy cases making a spontaneous recovery after primary inoculation. Observed and simulated case-histories are compared with respect to 9 descriptive statistics. The simulated courses of parasitaemia are more realistic than any previously published. The model uses a discrete time-step of 2 days. Its realistic behaviour was achieved by the following combination of features (i) intra-clonal antigenic variation, (ii) large variations of the variants' baseline growth rate, depending on both variant and case, (iii) innate autoregulation of the asexual parasite density, variable among cases, (iv) acquired variant-specific immunity and (v) acquired variant-transcending immunity, variable among cases. Aspects of the model's internal behaviour, concerning variant dynamics, as well as the respective contributions of the three control mechanisms (iii) - (v), are displayed. Some implications for pathogenesis and control are discussed.

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    • "While clinically immune cases are frequently asymptomatic or of low clinical virulence, data from malariatherapy studies suggest naïve cases may also have a wide range of clinical virulence ranging from high virulence to asymptomatic [24]. Other studies suggest that asymptomatic malaria is not limited to areas of high transmission where exposure-related immunity is expected to develop [25-27]. "
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    ABSTRACT: Despite a resurgence in control efforts, malaria remains a serious public-health problem, causing millions of deaths each year. One factor that complicates malaria-control efforts is clinical immunity, the acquired immune response that protects individuals from symptoms despite the presence of parasites. Clinical immunity protects individuals against disease, but its effects at the population level are complex. It has been previously suggested that under certain circumstances, malaria is bistable: it can persist, if established, in areas where it would not be able to invade. This phenomenon has important implications for control: in areas where malaria is bistable, if malaria could be eliminated until immunity wanes, it would not be able to re-invade. Here, we formulate an analytically tractable, dynamical model of malaria transmission to explore the possibility that clinical immunity can lead to bistable malaria dynamics. We summarize what is known and unknown about the parameters underlying this simple model, and solve the model to find a criterion that determines under which conditions we expect bistability to occur. We show that bistability can only occur when clinically immune individuals are more "effective" at transmitting malaria than naïve individuals are. We show how this "effectiveness" includes susceptibility, ability to transmit, and duration of infectiousness. We also show that the amount of extra effectiveness necessary depends on the ratio between the duration of infectiousness and the time scale at which immunity is lost. Thus, if the duration of immunity is long, even a small amount of extra transmission effectiveness by clinically immune individuals could lead to bistability. We demonstrate a simple, plausible mechanism by which clinical immunity may be causing bistability in human malaria transmission. We suggest that simple summary parameters - in particular, the relative transmission effectiveness of clinically immune individuals and the time scale at which clinical immunity is lost - are key to determining where and whether bistability is happening. We hope these findings will guide future efforts to measure transmission parameters and to guide malaria control efforts.
    BMC Infectious Diseases 09/2013; 13(1):428. DOI:10.1186/1471-2334-13-428 · 2.61 Impact Factor
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    • "Mathematical modelling of malaria made major leaps forward through the Garki Project and the model built to study it [22], as well as modern models for population dynamics which followed [23-27]. In addition to population-level models, recent research has advanced the state of detailed models of the within-host dynamics of Plasmodium falciparum[28-30]. Models have been constructed to study antigenic variation at the single infection level [31,32]. "
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    • "Among several mathematical models developed for P. falciparum blood infection (e.g. [91] [92] [93]) one model assumes that above a threshold parasite density var expression becomes less tightly controlled [93]. Merrick et al. propose a model in which the severity of disease depends on a degree of host stress response, leading among others to the observed elevated Pfsir2a and Pfsir2b transcripts (and assumes that protein levels are accordingly increased), which in turn contribute to the deregulation of var gene transcription [85]. "
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    ABSTRACT: The SIR2 family of NAD(+)-dependent protein deacetylases, collectively called sirtuins, has been of central interest due to their proposed roles in life-span regulation and ageing. Sirtuins are one group of environment sensors of a cell interpreting external information and orchestrating internal responses at the sub-cellular level, through participation in gene regulation mechanisms. Remarkably conserved across all kingdoms of life SIR2 proteins in several protozoan parasites appear to have both conserved and intriguing unique functions. This review summarises our current knowledge of the members of the sirtuin families in Apicomplexa, including Plasmodium, and other protozoan parasites such as Trypanosoma and Leishmania. The wide diversity of processes regulated by SIR2 proteins makes them targets worthy of exploitation in anti-parasitic therapies.
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