The impact of host stress on virulence phenotypes in the malaria parasite Plasmodium falciparum

Abstract

Plasmodium falciparum encodes a family of key virulence genes called var genes. These encode adhesive proteins that are expressed on infected erythrocytes in a mutually exclusive manner. The parasite’s sirtuins have been implicated in epigenetic selection of the expressed var gene(s). In field isolates, associations have been made between upregulation of sirtuins and two host stress factors that define severe malaria, and increased var gene expression. The parasite may specifically respond to these host factors, fever and hyperlactatemia, through sirtuins, leading to phenotypic variation.
In this thesis, both laboratory and field strains of P. falciparum were used to investigate these relationships in culture. Heat shock at 40°C can modestly increase the expression of PfSir2B in the trophozoite or PfSir2A in the ring stages. PfSir2B was also decreased in the rings. Severe disease associated var gene subsets, groups A, B and E, were predominantly upregulated upon stress or after the parasites were allowed to recover within one asexual cycle. There was a general upregulation of var transcript levels majorly after recovery. Thus, both upregulation of specific var gene subset and total var gene expression may manifest as strategies to cope with heat stress. High lactate exposure, meanwhile, had no clear association with sirtuin or var gene expression, suggesting that the in-vivo-observed association of high lactate concentration with the sirtuins and var genes appeared to be coincidental. Interestingly, however, lactate positively impacted parasite growth in culture at low parasitaemia. Finally, these stressors may reduce gametocytogenesis, which was investigated in one of the three field strains as it was able to produce gametocytes. The present study will inform the development of interventions against chronic or fatal severe falciparum malaria.