Oligopeptide Signaling through TbGPR89 Drives Trypanosome Quorum Sensing

Abstract

SummaryTrypanosome 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. Although trypanosomes lack G protein-coupled receptor signaling, we have identified a surface GPR89-family protein that regulates stumpy formation. TbGPR89 is expressed on bloodstream “slender form” trypanosomes, which receive the SIF signal, and when ectopically expressed, TbGPR89 drives stumpy formation in a SIF-pathway-dependent process. Structural modeling of TbGPR89 predicts unexpected similarity to oligopeptide transporters (POT), and when expressed in bacteria, TbGPR89 transports oligopeptides. Conversely, expression of an E. coli POT in trypanosomes drives parasite differentiation, and oligopeptides promote stumpy formation in vitro. Furthermore, the expression of secreted trypanosome oligopeptidases generates a paracrine signal that accelerates stumpy formation in vivo. Peptidase-generated oligopeptide QS signals being received through TbGPR89 provides a mechanism for both trypanosome SIF production and reception.

The zinc finger proteins ZC3H20 and ZC3H21 stabilise mRNAs encoding membrane proteins and mitochondrial proteins in insect‐form Trypanosoma brucei

“…These have a variant surface glycoprotein surface coat and depend mainly on glycolysis for ATP, using enzymes that are compartmentalised in a microbody called the glycosome (Hannaert, Bringaud, & Michels, ). When bloodstream forms reach high density, either in culture or in a mammal, they have a quorum sensing response (Rojas et al, ) and transform to nondividing stumpy form trypomastigotes. Upon uptake of the stumpy forms by Tsetse, or transfer to culture at 27°C in the presence of cis‐aconitate, stumpy forms develop into growing procyclic trypomastigotes, which rely mainly on mitochondrial pathways of ATP generation (Bringaud, Riviere, & Coustou, ; Mantilla et al, ).…”

The zinc finger proteins ZC3H20 and ZC3H21 stabilise mRNAs encoding membrane proteins and mitochondrial proteins in insect-formTrypanosoma brucei

“…These have a variant surface glycoprotein surface coat and depend mainly on glycolysis for ATP, using enzymes that are compartmentalised in a microbody called the glycosome (Hannaert et al, 2003). When bloodstream forms reach high density, either in culture or in a mammal, they have a quorum sensing response (Rojas et al, 2018) and transform to non-dividing stumpy-form trypomastigotes. Upon uptake of the stumpy forms by Tsetse, or transfer to culture at 27°C in the presence of cis-aconitate, stumpy forms develop into growing procyclic trypomastigotes, which rely mainly on mitochondrial pathways of ATP generation (Mantilla et al, 2017, Bringaud et al, 2006.…”

Trypanosoma brucei gambiense excreted/secreted factors impair lipopolysaccharide‐induced maturation and activation of human monocyte‐derived dendritic cells

“…The secretome, (excreted/secreted factors), of trypanosomes is a complex mixture of proteins, carbohydrates and lipids excreted from the surface of the parasite or secreted via exocytotic vesicles by a parasite‐specific organelle called the flagellar pocket . Some of these components are implicated in T brucei evasion of host innate response and others in the virulence process . Because of the fundamental role of DCs during trypanosomiasis but limited human data, we investigated the effects of T gambiense and its secretome on human monocytes‐derived DCs.…”

“…[12][13][14] Some of these components are implicated in T brucei evasion of host innate response 15,16 and others in the virulence process. [17][18][19][20][21] Because of the fundamental role of DCs during trypanosomiasis but limited human data, we investigated the effects of T gambiense and its secretome on human monocytes-derived DCs.…”