Cyclic AMP signalling and glucose metabolism mediate pH taxis by African trypanosomes

Sebastian Shaw,Sebastian Knüsel,Ruth Etzensperger,Arunasalam Naguleswaran,Isabel Roditi,Daniel Abbühl,Mattias Benninger

doi:10.1038/s41467-022-28293-w

Abstract

The collective movement of African trypanosomes on semi-solid surfaces, known as social motility, is presumed to be due to migration factors and repellents released by the parasites. Here we show that procyclic (insect midgut) forms acidify their environment as a consequence of glucose metabolism, generating pH gradients by diffusion. Early and late procyclic forms exhibit self-organising properties on agarose plates. While early procyclic forms are repelled by acid and migrate outwards, late procyclic forms remain at the inoculation site. Furthermore, trypanosomes respond to exogenously formed pH gradients, with both early and late procyclic forms being attracted to alkali. pH taxis is mediated by multiple cyclic AMP effectors: deletion of one copy of adenylate cyclase ACP5, or both copies of the cyclic AMP response protein CARP3, abrogates the response to acid, while deletion of phosphodiesterase PDEB1 completely abolishes pH taxis. The ability to sense pH is biologically relevant as trypanosomes experience large changes as they migrate through their tsetse host. Supporting this, a CARP3 null mutant is severely compromised in its ability to establish infections in flies. Based on these findings, we propose that the expanded family of adenylate cyclases in trypanosomes might govern other chemotactic responses in their two hosts.

Highlights

The collective movement of African trypanosomes on semi-solid surfaces, known as social motility, is presumed to be due to migration factors and repellents released by the parasites
We concentrated the supernatant of a dense culture (2 × 107 cells ml−1) 10-fold and spotted this “conditioned medium” (CM) next to migrating projections on social motility (SoMo) plates (Fig. 1a, upper panel)
We show for the first time that trypanosomes acidify their environment as a consequence of glucose metabolism, generating pH gradients by diffusion

Summary

Introduction

The collective movement of African trypanosomes on semi-solid surfaces, known as social motility, is presumed to be due to migration factors and repellents released by the parasites. Intracellular pathogens frequently exploit receptor-ligand interactions to recognise and invade the appropriate cell types[9,10,11,12] For extracellular parasites such as Trypanosoma brucei spp., causative agents of human and animal trypanosomiasis, it is not known what drives them to move from one host tissue to another. Various species of Leishmania, parasites related to trypanosomes, respond chemotactically to a range of compounds including amino acids, carbohydrates and sera, in liquid culture[22,23,24,25] In none of these cases is it known which genes mediate the responses. We show that procyclic forms can generate pH gradients through glucose metabolism and that the response of early and late procyclic forms to these gradients can explain the self-organising properties of communities on plates. PH sensing is completely abolished in PDEB1 knockout, where cAMP levels are perturbed

Methods

Results

Conclusion