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

Abstract

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.

The dynamics of acute malaria infections. I. Effect of the parasite's red blood cell preference

“…We also describe the dynamics of RBCs entirely as a consequence of loss following infection by merozoites. This suggests that the role of bystander destruction of uninfected RBCs ( Jakeman et al 1999;Haydon et al 2003) may need to be reconsidered, at least for the initial dynamics of P. chabaudi infections of mice.…”

“…Many models have indicated the importance of RBC limitation (Anderson et al 1989;Hellriegel 1992;Gravenor et al 1995;Hetzel & Anderson 1996;Mason et al 1999;Haydon et al 2003) but are not able to explain the observation that strains with identical growth rates generate different parasite densities and hence different degrees of anaemia. The need to consider the RBC age preference to explain infection dynamics has been emphasized in the modelling studies of McQueen & McKenzie (2004.…”

“…While most studies agree that specific immunity does not play a major role in this initial dynamics, there is considerable controversy over which factors drive the dynamics shortly after infection (Anderson et al 1989;Hellriegel 1992;Hetzel & Anderson 1996;McQueen & McKenzie 2004). Some of the hypotheses to explain the differences in the initial dynamics of malaria strains include (i) the conventional view-in both the virulence evolution and the malaria literature-that the fastest replicating parasites reach the highest densities and cause most anaemia (Antia et al 1994;Mason et al 1999;Chotivanich et al 2000;Gandon et al 2001), (ii) the hypothesis that strains infecting reticulocytes (the youngest RBCs) cause the severest anaemia (McQueen & McKenzie 2004, and (iii) the hypothesis that innate or early specific immune responses regulate the initial dynamics of infection and anaemia ( Jakeman et al 1999;Haydon et al 2003;Dietz et al 2006).…”

The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy

“…Instead, the competition between coinfecting malaria parasites probably arises from competition for resources. Most likely, this competition is for access to red blood cells (44,(46)(47)(48)(49)(50)(51)(52)(53), although other resources, such as glucose, may also be involved (40). Immune-mediated apparent competition, wherein the immune response provoked by one strain suppresses the population densities of a coinfecting strain (11), likely also plays a major role (41,54).…”

Ecological rules governing helminth–microparasite coinfection

“…One major finding is that the relative importance of top-down and bottom-up control mechanisms varies among species and ecosystems; a charismatic example of this is provided by African savannah systems, in which zebra populations are primarily controlled by predators, whereas wildebeest are more strongly regulated by the quality and quantity of plant matter available for them to eat (18). I applied these principles on a different scale in the present study, to investigate whether defined within-host ecological interactions, namely, competition for resources (bottom-up population control) and/or predation by the immune system (top-down control) (22), could explain changes in microparasite population size caused by underlying helminth coinfection. I essentially undertook analysis of the community ecology of the coinfected laboratory mouse.…”