Immunopathology and virulence evolution in rodent malaria

From an evolutionary perspective, natural selection is expected to maximize transmission to new hosts. If a live, mobile host often benefits parasite transmission, the question arises as to why malaria parasites are virulent? The favoured trade-off view of virulence evolution assumes that virulence arises as an unavoidable consequence of parasite resource exploitation within the host that is necessary to maximise parasite transmission. However, virulence is not always a simple function of parasite density and can arise as a result of immune-mediated virulence (immunopathology). This thesis explores how immunopathology contributes to virulence on the one hand, and parasite transmission on the other, in order to improve our understanding of parasite virulence evolution. In tackling this question, the role parasite genetic diversity plays in determining immunopathology induced during malaria infection was also addressed. Using the rodent malaria Plasmodium chabaudi chabaudi (P.c.c.) in C57BL/6 mice, I explored whether immune factors – in terms of specific host cytokines central to the protection-pathology balancing act of the immune response elicited against malaria parasites – help to determine the virulence induced during infection with genetically distinct parasites, and if so, what effect this may have on transmission-stage parasites. I showed that the cytokine milieu induced by P.c.c. parasites during primary infection varies with parasite genotype and that virulence can arise independent of parasite density, via immunopathology. Specifically, I showed propensity to induce the pro-inflammatory cytokine tumour necrosis factor [TNF]-a contributes to the virulence induced, regardless of P.c.c. clone. Importantly, I also showed that across P.c.c. genotype, TNF-a reduces the density of transmission-stage parasites. Thus, virulence is not always a simple function of parasite replication, having an immune-mediated component which acts to reduce transmission potential. The importance of parasite genotype in determining the degree of immunopathological virulence induced during malaria infection was revealed by studying the anti-inflammatory arm of the immune response. The extent to which the anti-inflammatory cytokines interleukin [IL]-10 or transforming growth factor [TGF]-b limited the immunopathology induced during P.c.c. infection depended on parasite clone. In addition, parasite genotype played a key role in determining how such anti-inflammatory manipulations affected the density of transmission-stage parasites; being detrimental, beneficial or incidental to parasite fitness, depending on P.c.c. clone. Although the general mechanisms of immune regulation are qualitatively unchanged across distinct P.c.c. clones, these data emphasize the importance of parasite genotype: distinct clones differ quantitatively in immune regulation, which contributes towards their distinct virulence and fitness schedules. Overall, I found that even within a parasite species – in this case P. chabaudi – the effect of immunopathology on the virulence-transmissibility relationship may be genetically variable and may not conform to that predicted by the trade-off hypothesis, having the potential to alter the costs and benefits of virulence, depending on parasite genotype. Thus, the host immune response may play a role shaping virulence evolution and defining the limit to malaria virulence in nature