Differentiation of African trypanosomes is controlled by a density sensing mechanism which signals cell cycle arrest via the cAMP pathway

Abstract

Differentiation of African trypanosomes from replicating slender bloodstream forms to nondividing stumpy forms limits the parasite population size, allowing survival of the mammalian host and establishment of a stable host-parasite relationship. Using a novel in vitro culture system we have shown that slender to stumpy differentiation is induced by parasite density alone and thus is independent of host cues. Here we investigate the density sensing mechanism and show that trypanosomes release a soluble activity of low relative molecular mass, termed stumpy induction factor (SIF), which accumulates in conditioned medium. SIF activity triggers cell cycle arrest in G1/G0 phase and induces differentiation with high efficiency and rapid kinetics. Membrane-permeable derivates of cAMP or the phosphodiesterase inhibitor etazolate perfectly mimic SIF activity. Furthermore, SIF activity elicits an immediate two- to threefold elevation of intracellular cAMP content upon addition to slender forms. We conclude that SIF and hence density sensing operate through the cAMP signalling pathway. Temporal correlation of markers indicates that cell cycle arrest invariably precedes differentiation. Thus, our results indicate that the cell cycle regulation of bloodstream forms is under dominant control of cAMP signalling. Irreversible commitment to the quiescent state is elicited by a cAMP agonist within a period shorter than one complete cell cycle.

Parasite co-infection: an ecological, molecular and experimental perspective

“…Quorum sensing is best understood in bacteria where a variety of signalling mechanisms are known, but also plays a role in the community behaviour of diverse eukaryotic pathogens. For example, the development of T. brucei from a proliferative slender form to a transmission-adapted stumpy form in its mammal host is regulated by quorum sensing via ‘stumpy induction factor' activity [ 71 , 72 ]. This has been found to comprise oligopeptide signals generated by parasite-released peptidases [ 73 ], with intracellular signalling pathway components required for quorum sensing also identified [ 74 ].…”

Salivarian Trypanosomes Have Adopted Intricate Host-Pathogen Interaction Mechanisms That Ensure Survival in Plain Sight of the Adaptive Immune System

“…In order to avoid this, trypanosomes have developed quorum sensing mechanisms that have been studied best for T. brucei. This system regulates the transition from the dividing long slender bloodstream forms to the non-dividing short stumpy forms [25]. It involves the oligopeptidase transporter TbGPR89 as a 'sensor' for peptide breakdown products, an activity attributed to the action of proteases secreted by the parasite [26].…”

Oxidative Phosphorylation Is Required for Powering Motility and Development of the Sleeping Sickness Parasite Trypanosoma brucei in the Tsetse Fly Vector

“…Long slender BSF T. brucei organisms differentiate to the cell cycle-arrested stumpy BSF upon reaching high parasite numbers, induced by quorum sensing ( 20 – 22 ). The stumpy form is preadapted to survival in the tsetse fly vector by being more resistant to pH and proteolytic stresses and by beginning to prepare its mitochondrial energy metabolism for the change in nutrient availability.…”