Characterisation of the thermal and non-thermal stress conditions that activate the Plasmodium falciparum AP2-HS-dependent heat-shock response.

To preserve proteome homeostasis and survive at higher-than-optimal temperatures, organisms have evolved the conserved heat-shock (HS) response (HSR), characterised by increased expression of specific chaperone-encoding genes. In the human blood, malaria parasites are frequently exposed to elevated temperatures associated with host fever episodes. The protective HSR of Plasmodium falciparum, the parasite that produces the vast majority of malaria clinical cases and deaths, is regulated by the transcription factor AP2-HS. Here, we systematically investigated the conditions that trigger the AP2-HS-dependent HSR and found that even mild HS conditions that do not compromise parasite viability can activate this response. As in other organisms, activation of the HSR in P. falciparum is rapid, as it was observed after a HS of only 10 min. Dihydroartemisinin (DHA), a drug that produces general proteome damage, also triggered the HSR, indicating that activation of the malarial HSR is not restricted to thermal stress. The AP2-HS-dependent HSR can be activated in all asexual blood stages, with the exception of very young rings, but not in intermediate or mature gametocyte stages. Accordingly, these gametocyte stages are highly sensitive to HS. Since mature gametocytes are the only stage that can mediate human-to-mosquito transmission, these results suggest that malaria patients with high fever may become transiently non-infectious.