Thermo-related degeneration of stumpy forms of Trypanosoma brucei, the pathogen of African sleeping sickness.

Trypanosoma brucei, the causative agent of African trypanosomiasis, develops from the long slender (LS) to the short stumpy (SS) form in the mammalian host. The SS trypanosomes are critical for transmission to the insect vector but face significant challenges within the vertebrate host. The role of the immune response in controlling the parasitaemia is well studied, however, the mechanism underpinning the rapid degeneration of SS trypanosomes during the first parasitaemic peak in mice remains somewhat elusive. We demonstrate that fever is a critical yet underexplored factor in facilitating the clearance of SS trypanosomes, suggesting that temperature may play a critical role in regulating the natural turnover of SS trypanosomes. The elevated body temperature correlates with the parasitaemic dynamics, accelerating SS trypanosome elimination in the mammalian host. The SS trypanosomes exhibited high thermo-sensitivity to elevated temperatures, accompanied with apoptosis-like events, mitochondrial damage and oxidative stress. Metabolomic profiling also revealed disruptions in glycolysis and the TCA cycle, shedding light on the processes in compromising the SS trypanosomes. Interestingly, antibodies during the acute phase did not directly cause SS trypanosomes death, but the combination of elevated temperature and antibodies enhanced the clearance of SS trypanosomes, highlighting the critical role of fever in eliminating the first parasitaemic peak. Our findings detail the mechanism of vulnerability of SS trypanosome to elevated temperatures and suggest that host fever serves as a neglected, but critical mechanism, for T. brucei SS trypanosome clearance.