Transient temperature fluctuations severely decrease P. falciparum susceptibility to artemisinin in vitro

Clinical studies suggest that outcomes for hospitalised malaria patients can be improved by managed hypothermia during treatment. We examined the impact of short pulses of low temperature on ring-stage susceptibility of Plasmodium falciparum to artemisinin in vitro. The usually artemisinin-sensitive clone 3D7 exhibited substantially reduced ring-stage susceptibility to a 4-h pulse of 700 nM dihydro-artemisinin administered during a 5-h pulse of low temperature down to 17 °C. Parasite growth through the subsequent asexual cycle was not affected by the temperature pulse. Chloroquine and pyronaridine susceptibility, in a standard 48-h test, was not affected by brief exposures to low temperature. Fever-like temperature pulses up to 40 °C were also accompanied by enhanced ring-stage survival of 700 nM artemisinin pulses, but parasite growth was generally attenuated at this temperature. We discuss these findings in relation to the possible activation of parasite stress responses, including the unfolded protein response, by hypo- or hyper-thermic conditions. Physiological states may need to be considered in artemisinin-treated P. falciparum patients.