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

• Published in: International journal for parasitology -- drugs and drug resistance Vol. 9; pp. 23 - 26
• Main Authors: Henrici, Ryan C., van Schalkwyk, Donelly A., Sutherland, Colin J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2019; Elsevier
• Subjects: Antimalarials - pharmacology; Artemisinins - pharmacology; Cold Temperature; Parasitic Sensitivity Tests; Plasmodium falciparum - drug effects; Plasmodium falciparum - growth & development; Stress, Physiological; Unfolded Protein Response
• ISSN: 2211-3207; 2211-3207
• DOI: 10.1016/j.ijpddr.2018.12.003

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. Effect of transient hypothermia on ring-stage artemisinin susceptibility of P. falciparum clone 3D7. Ring-stage survival (proportion of control) of DHA pulse-treated 3D7 parasites (black circles) transiently incubated at hypothermic and normothermic temperatures. Open circles represent RSA survival estimates, in our hands, for previously described Cambodian parasite lines Cam 3.11 (reduced DHA susceptibility) and Cam 3.11REV (fully DHA susceptible), with K13 genotypes in superscript. P value was estimated by two-sided t-test between 17 °C (n = 4) and 37 °C (n = 6) (mean difference 58.7% survival; 95% CI 57.7–59.8% survival; 8 d.f.). [Display omitted]