Glycerol metabolism triggers trypanosome differentiation into transmissible forms in mammalian tissue-like conditions

In the mammalian host, Trypanosoma brucei proliferates as slender bloodstream forms before undergoing quorum-sensing (QS)-dependent differentiation into non-dividing transmissible stumpy-QS forms, a process that both controls parasitaemia and enables transmission to the tsetse fly. However, this model does not explain how transmission occurs in chronically infected patients and cattle, where parasite densities are often too low to trigger QS-mediated differentiation. We identify a relevant glycerol-dependent pathway driven by adipocyte-derived glycerol that offers an explanation for this transmission paradox. We show that, at low parasite density, and with physiological levels of glycerol (0.2 mM) and glucose (4 mM) mimicking adipose and hypodermal interstitial fluids, glycerol promotes the emergence of novel proliferative forms that we termed, slender-Glyc forms. These cells are transmissible, unlike the slender forms, since they (i) differentiate in vitro into procyclic forms, which appear in the midgut of the infected flies, and (ii) establish infections in the fly. In addition, at high parasite density, tissular amounts of glycerol extends the lifespan of stumpy-QS forms (named stumpy-QS/Glyc), increasing transmission chances for tissue parasites, especially in the skin. Altogether, our findings suggest that local metabolic conditions, either on their own or in combination with parasite density, can drive transmission capacity.