Trypanosome parasites control their virulence and spread by using quorum sensing (QS) to generate transmissible “stumpy forms” in their host bloodstream. However, the QS signal “stumpy induction factor” (SIF) and its reception mechanism are unknown.
Researchers studied how parasites in the bloodstream send chemical signals to one another to undergo a physical change (stumpy) that is needed for them to spread disease. Scientists found that the parasites release enzymes, called peptidases, which break down proteins in the blood into smaller molecules.
These small molecules, known as oligopeptides, are sensed by a protein - GPR89 - which is found on the surface of the parasite. This triggers the parasites' transition into a stumpy state in which they can be taken up and transmitted by flies. Oligopeptides also act as nutrients for the parasites and are taken up by the same surface protein.
Structural modeling of GPR89 predicts unexpected similarity to oligopeptide transporters (POT), and when expressed in bacteria, GPR89 transports oligopeptides. Conversely, expression of an E. coli POT in trypanosomes drives parasite differentiation, and oligopeptides promote stumpy formation in vitro. The expression of secreted trypanosome oligopeptidases generates a paracrine signal that accelerates stumpy formation in vivo.
Disrupting this process by designing drugs that interfere with the GPR89 protein could offer a new way of tackling the disease, the team suggests.
The approach could limit drug resistance in two ways - by restricting the supply of nutrients and stopping transition to the state required for disease to spread, researchers say.
Researchers also suggest that the parasites could be disarmed by an artificial form of the signalling molecule. This would trick the parasites into prematurely arresting their growth. The study was published in journal Cell.
A new mechanism to increase Trypanosoma parasite virulence
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