Bloodstream form pre-adaptation to the tsetse fly in Trypanosoma brucei

Abstract

African trypanosomes are sustained in the bloodstream of their mammalian hosts by their extreme capacity for antigenic variation. However, for life cycle progression, trypanosomes also must generate transmission stages called stumpy forms that are pre-adapted to survive when taken up during the bloodmeal of the disease vector, tsetse flies. These stumpy forms are rather different to the proliferative slender forms that maintain the bloodstream parasitaemia. Firstly, they are non proliferative and morphologically distinct, secondly, they show particular sensitivity to environmental cues that signal entry to the tsetse fly and, thirdly, they are relatively robust such that they survive the changes in temperature, pH and proteolytic environment encountered within the tsetse midgut. These characteristics require regulated changes in gene expression to pre-adapt the parasite and the use of environmental sensing mechanisms, both of which allow the rapid initiation of differentiation to tsetse midgut procyclic forms upon transmission. Interestingly, the generation of stumpy forms is also regulated and periodic in the mammalian blood, this being governed by a density-sensing mechanism whereby a parasite-derived signal drives cell cycle arrest and cellular development both to optimize transmission and to prevent uncontrolled parasite multiplication overwhelming the host. In this review we detail recent developments in our understanding of the molecular mechanisms that underpin the production of stumpy forms in the mammalian bloodstream and their signal perception pathways both in the mammalian bloodstream and upon entry into the tsetse fly. These discoveries are discussed in the context of conserved eukaryotic signaling and differentiation mechanisms. Further, their potential to act as targets for therapeutic strategies that disrupt parasite development either in the mammalian bloodstream or upon their transmission to tsetse flies is also discussed.

The proteome and transcriptome of the infectious metacyclic form of Trypanosoma brucei define quiescent cells primed for mammalian invasion

“…Previous experiments in BF cells have demonstrated that VSGs cannot be expressed from two different expression sites at the same high level without a penalty on cellular fitness (Chaves et al ., ; Batram et al ., ). Additionally, BF cells developing to quiescent stumpy forms (Vassella et al ., ; Capewell et al ., ; Rico et al ., ) have the VSG coat present on their surface, in contrast to MF cells that synthesize the VSG coat de novo during their transition to quiescence. Since (i) both MESs and BESs are Pol I gene expression units that produce about 10% of the mRNA and protein in the cell, (ii) compete for binding to the same general transcription initiation factor CITFA (Kolev et al ., ) and (iii) contain very similar VSG pre‐mRNA trans ‐splicing and polyadenylation signals, the choice of MESs over BESs in these cells transitioning to quiescence indicates that not only they cannot support the expression of more than one VSG expression site, but they also cannot support the expression of a single 40–60 kb long BES.…”

Mammalian African trypanosome VSG coat enhances tsetse’s vector competence

“…In contrast, stumpy forms, which are preadapted for survival in tsetse, receive an unknown signal and differentiate to insect-stage procyclic forms (reviewed in ref. 38). Stumpy parasites release their VSG coat via a bimodal process that involves GPI hydrolysis by a parasite GPI phospholipase C and endoproteolytic cleavage (39,40).…”

Metabolic reprogramming during the Trypanosoma brucei life cycle

“…These adaptions also include increased sensitivity to specific environmental cues that signal entry to the tsetse fly vector, as well as resistance to extracellular acidic and proteolytic stress 40, 41 . Given that B-SS are non-proliferative and existent only in pleomorphic strains, it is more difficult to obtain large and pure quantities of this life-cycle stage in vitro .…”