Dataset Information

Depletion of FoxP3⁺ Tregs improves control of larval Echinococcus multilocularis infection by promoting co-stimulation and Th1/17 immunity.

ABSTRACT:

Introduction

The growth potential of the tumor-like Echinococcus multilocularis metacestode (causing alveolar echinococcosis, AE) is directly linked to the nature/function of the periparasitic host immune-mediated processes. Previous studies had shown that regulatory T cells (Tregs) become gradually up-regulated in the course of both chronic human and murine AE. Thus we now tackled the role of FoxP3⁺ Tregs and FoxP3⁺ -Treg-regulated immune response in contributing to the control of this helminthic infection.

Methods

The infection outcome in E. multilocularis-infected DEREG mice was measured upon determining parasite load (wet weight of parasitic metacestode tissue). Flow cytometry and qRT-PCR were used to assess Treg, Th17-, Th1-, Th2-type immune responses and antigen presenting cell activation.

Results

We showed that E. multilocularis-infected DEREG-mice treated with DT (as compared to infected control DEREG-mice without DT application) exhibited a significantly lower parasite load, associated with a persisting capacity of co-stimulation, and an increased Th1/Th17-polarization.

Conclusions

FoxP3⁺ Tregs appear as one of the key players in immune regulatory processes favoring (i) metacestode survival by inhibiting the maturation potential of co-stimulatory activity and (ii) T cell exhaustion (suppressing Th1/Th17-type immune responses). We showed as well that prospectively, targeting FoxP3⁺ Tregs could be an option to develop an immunotherapy against AE.

SUBMITTER: Wang J

PROVIDER: S-EPMC5691311 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Publications

Depletion of FoxP3<sup>+</sup> Tregs improves control of larval Echinococcus multilocularis infection by promoting co-stimulation and Th1/17 immunity.

Wang Junhua J Müller Stephan S Lin Renyong R Siffert Myriam M Vuitton Dominique A DA Wen Hao H Gottstein Bruno B

Immunity, inflammation and disease 20170616 4

<h4>Introduction</h4>The growth potential of the tumor-like Echinococcus multilocularis metacestode (causing alveolar echinococcosis, AE) is directly linked to the nature/function of the periparasitic host immune-mediated processes. Previous studies had shown that regulatory T cells (Tregs) become gradually up-regulated in the course of both chronic human and murine AE. Thus we now tackled the role of FoxP3<sup>+</sup> Tregs and FoxP3<sup>+</sup> -Treg-regulated immune response in contributing t ...[more]

PMID: 28621034

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Project description:BackgroundSerotonin is a phylogenetically ancient molecule that is widely distributed in most metazoans, including flatworms. In addition to its role as a neurotransmitter, serotonin acts as a morphogen and regulates developmental processes. Although several studies have focused on the serotonergic nervous system in parasitic flatworms, little is known on the role of serotonin in flatworm development.MethodsTo study the effects of serotonin on proliferation and development of the cestode Echinococcus multilocularis, we cloned the genes encoding the E. multilocularis serotonin transporter (SERT) and tryptophan hydroxylase (TPH), analyzed gene expression by transcriptome analysis and whole mount in situ hybridization (WMISH) and performed cell culture experiments.ResultsWe first characterized orthologues encoding the SERT and TPH, the rate-limiting enzyme in serotonin biosynthesis. WMISH and transcriptomic analyses indicated that the genes for both SERT and TPH are expressed in the parasite nervous system. Long-term treatment of parasite stem cell cultures with serotonin stimulated development towards the parasite metacestode stage. Mature metacestode vesicles treated with serotonin showed increased rates of incorporation of the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU), indicating stimulated cell proliferation. In contrast, treatment with the selective serotonin reuptake inhibitor paroxetine strongly affected the viability of parasite cells. Paroxetine also caused structural damage in metacestode vesicles, suggesting that serotonin transport is crucial for the integrity of parasite vesicles.ConclusionsOur results indicate that serotonin plays an important role in E. multilocularis development and proliferation, providing evidence that the E. multilocularis SERT and TPH are expressed in the nervous system of the protoscolex. Our results further suggest that the E. multilocularis SERT has a secondary role outside the nervous system that is essential for parasite integrity and survival. Since serotonin stimulated E. multilocularis metacestode development and proliferation, serotonin might also contribute to the formation and growth of the parasite in the liver.

Project description:BACKGROUND: The metacestode of the tapeworm Echinococcus multilocularis is the causative agent of alveolar echinococcosis, a lethal zoonosis. Infections are initiated through establishment of parasite larvae within the intermediate host's liver, where high concentrations of insulin are present, followed by tumour-like growth of the metacestode in host organs. The molecular mechanisms determining the organ tropism of E. multilocularis or the influences of host hormones on parasite proliferation are poorly understood. RESULTS: Using in vitro cultivation systems for parasite larvae we show that physiological concentrations (10 nM) of human insulin significantly stimulate the formation of metacestode larvae from parasite stem cells and promote asexual growth of the metacestode. Addition of human insulin to parasite larvae led to increased glucose uptake and enhanced phosphorylation of Echinococcus insulin signalling components, including an insulin receptor-like kinase, EmIR1, for which we demonstrate predominant expression in the parasite's glycogen storage cells. We also characterized a second insulin receptor family member, EmIR2, and demonstrated interaction of its ligand binding domain with human insulin in the yeast two-hybrid system. Addition of an insulin receptor inhibitor resulted in metacestode killing, prevented metacestode development from parasite stem cells, and impaired the activation of insulin signalling pathways through host insulin. CONCLUSIONS: Our data indicate that host insulin acts as a stimulant for parasite development within the host liver and that E. multilocularis senses the host hormone through an evolutionarily conserved insulin signalling pathway. Hormonal host-parasite cross-communication, facilitated by the relatively close phylogenetic relationship between E. multilocularis and its mammalian hosts, thus appears to be important in the pathology of alveolar echinococcosis. This contributes to a closer understanding of organ tropism and parasite persistence in larval cestode infections. Furthermore, our data show that Echinococcus insulin signalling pathways are promising targets for the development of novel drugs.

Project description:BackgroundThe metacestode larva of Echinococcus multilocularis (Cestoda: Taeniidae) develops in the liver of intermediate hosts (typically rodents, or accidentally in humans) as a labyrinth of interconnected cysts that infiltrate the host tissue, causing the disease alveolar echinococcosis. Within the cysts, protoscoleces (the infective stage for the definitive canid host) arise by asexual multiplication. These consist of a scolex similar to that of the adult, invaginated within a small posterior body. Despite the importance of alveolar echinococcosis for human health, relatively little is known about the basic biology, anatomy and development of E. multilocularis larvae, particularly with regard to their nervous system.ResultsWe describe the existence of a subtegumental nerve net in the metacestode cysts, which is immunoreactive for acetylated tubulin-α and contains small populations of nerve cells that are labeled by antibodies raised against several invertebrate neuropeptides. However, no evidence was found for the existence of cholinergic or serotoninergic elements in the cyst wall. Muscle fibers occur without any specific arrangement in the subtegumental layer, and accumulate during the invaginations of the cyst wall that form brood capsules, where protoscoleces develop. The nervous system of the protoscolex develops independently of that of the metacestode cyst, with an antero-posterior developmental gradient. The combination of antibodies against several nervous system markers resulted in a detailed description of the protoscolex nervous system, which is remarkably complex and already similar to that of the adult worm.ConclusionsWe provide evidence for the first time of the existence of a nervous system in the metacestode cyst wall, which is remarkable given the lack of motility of this larval stage, and the lack of serotoninergic and cholinergic elements. We propose that it could function as a neuroendocrine system, derived from the nervous system present in the bladder tissue of other taeniids. The detailed description of the development and anatomy of the protoscolex neuromuscular system is a necessary first step toward the understanding of the developmental mechanisms operating in these peculiar larval stages.

Dataset Information

Depletion of FoxP3⁺ Tregs improves control of larval Echinococcus multilocularis infection by promoting co-stimulation and Th1/17 immunity.

Introduction

Methods

Results

Conclusions

Publications

Depletion of FoxP3<sup>+</sup> Tregs improves control of larval Echinococcus multilocularis infection by promoting co-stimulation and Th1/17 immunity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Depletion of FoxP3+ Tregs improves control of larval Echinococcus multilocularis infection by promoting co-stimulation and Th1/17 immunity.

Introduction

Methods

Results

Conclusions

Publications

Depletion of FoxP3<sup>+</sup> Tregs improves control of larval Echinococcus multilocularis infection by promoting co-stimulation and Th1/17 immunity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Depletion of FoxP3⁺ Tregs improves control of larval Echinococcus multilocularis infection by promoting co-stimulation and Th1/17 immunity.