Cell-cell communication in African trypanosomes

Abstract

Years of research have shown us that unicellular organisms do not exist entirely in isolation, but rather that they are capable of an altogether far more sociable way of living. Single cells produce, receive and interpret signals, coordinating and changing their behaviour according to the information received. Although this cell-cell communication has long been considered the norm in the bacterial world, an increasing body of knowledge is demonstrating that single-celled eukaryotic parasites also maintain active social lives. This communication can drive parasite development, facilitate the invasion of new niches and, ultimately, influence infection outcome. In this review, I present the evidence for cell-cell communication during the life cycle of the African trypanosomes, from their mammalian hosts to their insect vectors, and reflect on the many remaining unanswered questions in this fascinating field.

Keywords: African trypanosomes; cell–cell communication; coinfection; extracellular vesicles; quorum sensing; social motility.

Fig. 1.

Summary of T. brucei slender-to-stumpy differentiation via the QS signalling pathway. Open research questions are posed for the appropriate stages of the QS response. Proliferative ‘slender’ cells secrete peptidases into the extracellular environment via an unknown mechanism. QS-relevant oligopeptides are predominantly generated by two peptidases and accumulate with increasing parasite density. Oligopeptides are transported into the trypanosome via the surface transporter TbGPR89 and begin the QS signalling cascade, resulting in the production of cell cycle-arrested ‘stumpy’ forms. A lncRNA, grumpy, contributes towards slender-to-stumpy differentiation regulation and binds at least one member of the QS pathway.

Fig. 2.

(a) Characteristics of SoMo-positive and -negative cells. (b) Summary of SoMo phenotypes for in vitro and in vivo tested conditions. Graphic depicts SoMo migration patterns on semi-solid agar plates. Genes/growth conditions on the right have been validated in vitro. Genes that have additionally been tested for their ability to impact on/block parasite migration from the endoperitrophic space to the ectoperitrophic space in vivo have been underlined. KD, knockdown; KO, knockout; cKO, conditional knockout.

Fig. 3.

Proposed biological roles for (a) BSF and (b) PCF T. brucei EVs, based on in vitro evidence. (a) BSF T. brucei EVs are proposed to do the following (i–iii). (i) Mediate virulence factor transfer between neighbouring trypanosomes. Upon induction of stress in vitro, purified T. b. brucei EVs were shown to contain multiple flagellar and membrane proteins that were known virulence factors. In addition, T. b. rhodesiense (resistant to human serum) EVs were shown to confer human serum resistance to T. b. brucei (human serum-susceptible) cells through the transfer of SRA. (ii) Transfer virulence factors to host cells. T. b. brucei EVs fused with host RBCs and incorporated VSG protein into the lipid membrane, changing the biophysical properties. (iii) Modulate the host immune response. T. brucei EVs established communication with mouse mononuclear cells and influenced both the innate and adaptive arms of immunity. This is proposed to help establish an environment that promotes trypanosome perseverance without overwhelming the host. (b) When synthesis of SL RNA was blocked, PCF cells released EVs that were capable of blocking SoMo of WT PCF cells in vitro.

Fig. 4.

The experimentally validated consequences (for the host and the trypanosome) of intra- and interspecies communication during infection. The consequences in the top panel have been validated in experimental animal infections. The consequences in the bottom panel have been validated by field data.