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Why is malaria not a more serious disease?
This question is important for all infectious agents. We know of no quantitative data demonstrating the source of selection against nastier parasites.
In the context of rodent malaria, we have demonstrated (Mackinnon and Read 1999, Mackinnon and Read 2002, Ferguson et al. in press) that more virulent malaria infections are more infectious to mosquitoes. Why has natural selection not produced hyperpathogenic malaria? Case fatality rates in the section of human populations responsible for the bulk of malaria transmission (and hence evolution) are very hard to estimate, but they may be somewhere between 10% and 1% or even less. Why is natural selection not making the disease nastier?
Conventional wisdom presumes that parasites are not hyper-virulent because, by killing their host, they kill themselves. However, the key issue is not mortality risk per se, but rather how increased risk of host death is traded off against the increased transmission benefits of virulence in the absence of host death. From our mouse experiments, we can say that case fatality rates of up to 80% are not enough to prevent the evolution of increased virulence (Mackinnon and Read 1999). But to determine whether host death is preventing the evolution of more virulent P. falciparum, we need to know the fitness function for P. falciparum, which can not be determined ethically.
There are other possible upper bounds on virulence. First, there may be parasite-derived limits to high virulence. For instance, virulent strains may reduce red blood cell densities to the point where gametocyte densities become limiting. A second possible bound is host genetics. The notion that the fitness (and virulence) of a particular pathogen genotype depends on the genotype of their host underpins ideas of coevolution. Host genotype by parasite genotype (G x G) interactions could limit virulence if lines that are virulent (fitter) in one host genotype are avirulent in another, and vice versa.
A third possible bound on virulence evolution is that, while more virulent clones infect more mosquitoes, they infect some of them sufficiently heavily to kill them, thus reducing the fitness benefits of virulence in the vertebrate host. Our work to date does not support this (Ferguson et al. in press).
Group members involved: Andy Bell
Collaborators: Margaret Mackinnon