Differential drivers of intraspecific and interspecific competition during malaria-helminth co-infection.

Various host and parasite factors interact to determine the outcome of infection. We investigated the effects of two factors on the within-host dynamics of malaria in mice: initial infectious dose and co-infection with a helminth that limits the availability of red blood cells (RBCs). Using a statistical, time-series approach to model the within-host 'epidemiology' of malaria, we found that increasing initial dose reduced the time to peak cell-to-cell parasite propagation, but also reduced its magnitude, while helminth co-infection delayed peak cell-to-cell propagation, except at the highest malaria doses. Using a mechanistic model of within-host infection dynamics, we identified dose-dependence in parameters describing host responses to malaria infection and uncovered a plausible explanation of the observed differences in single vs co-infections. Specifically, in co-infections, our model predicted a higher background death rate of RBCs. However, at the highest dose, when intraspecific competition between malaria parasites would be highest, these effects of co-infection were not observed. Such interactions between initial dose and co-infection, although difficult to predict a priori, are key to understanding variation in the severity of disease experienced by hosts and could inform studies of malaria transmission dynamics in nature, where co-infection and low doses are the norm.

Revealing mechanisms underlying variation in malaria virulence: effective propagation and host control of uninfected red blood cell supply.

Malaria parasite clones with the highest transmission rates to mosquitoes also tend to induce the most severe fitness consequences (or virulence) in mammals. This is in accord with expectations from the virulence-transmission trade-off hypothesis. However, the mechanisms underlying how different clones cause virulence are not well understood. Here, using data from eight murine malaria clones, we apply recently developed statistical methods to infer differences in clone characteristics, including induction of differing host-mediated changes in red blood cell (RBC) supply. Our results indicate that the within-host mechanisms underlying similar levels of virulence are variable and that killing of uninfected RBCs by immune effectors and/or retention of RBCs in the spleen may ultimately reduce virulence. Furthermore, the correlation between clone virulence and the degree of host-induced mortality of uninfected RBCs indicates that hosts increasingly restrict their RBC supply with increasing intrinsic virulence of the clone with which they are infected. Our results demonstrate a role for self-harm in self-defence for hosts and highlight the diversity and modes of virulence of malaria.

Virulence evolution and the trade-off hypothesis: history, current state of affairs and the future.

It has been more than two decades since the formulation of the so-called 'trade-off' hypothesis as an alternative to the then commonly accepted idea that parasites should always evolve towards avirulence (the 'avirulence hypothesis'). The trade-off hypothesis states that virulence is an unavoidable consequence of parasite transmission; however, since the 1990s, this hypothesis has been increasingly challenged. We discuss the history of the study of virulence evolution and the development of theories towards the trade-off hypothesis in order to illustrate the context of the debate. We investigate the arguments raised against the trade-off hypothesis and argue that trade-offs exist, but may not be of the simple form that is usually assumed, involving other mechanisms (and life-history traits) than those originally considered. Many processes such as pathogen adaptation to within-host competition, interactions with the immune system and shifting transmission routes, will all be interrelated making sweeping evolutionary predictions harder to obtain. We argue that this is the heart of the current debate in the field and while species-specific models may be better predictive tools, the trade-off hypothesis and its basic extensions are necessary to assess the qualitative impacts of virulence management strategies.