Extracellular vesicles from a helminth parasite suppress macrophage activation and constitute an effective vaccine for protective immunity

Coakley, G., McCaskill, J. L., Borger, J. G., Simbari, F., Robertson, E., Millar, M., Harcus, Y., McSorley, H. J., Maizels, R. M. and Buck, A. H. (2017) Extracellular vesicles from a helminth parasite suppress macrophage activation and constitute an effective vaccine for protective immunity. Cell Reports, 19(8), pp. 1545-1557. (doi:10.1016/j.celrep.2017.05.001) (PMID:28538175) (PMCID:PMC5457486)

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Abstract

Recent studies have demonstrated that many parasites release extracellular vesicles (EVs), yet little is known about the specific interactions of EVs with immune cells or their functions during infection. We show that EVs secreted by the gastrointestinal nematode Heligmosomoides polygyrus are internalized by macrophages and modulate their activation. EV internalization causes downregulation of type 1 and type 2 immune-response-associated molecules (IL-6 and TNF, and Ym1 and RELMα) and inhibits expression of the IL-33 receptor subunit ST2. Co-incubation with EV antibodies abrogated suppression of alternative activation and was associated with increased co-localization of the EVs with lysosomes. Furthermore, mice vaccinated with EV-alum generated protective immunity against larval challenge, highlighting an important role in vivo. In contrast, ST2-deficient mice are highly susceptible to infection, and they are unable to clear parasites following EV vaccination. Hence, macrophage activation and the IL-33 pathway are targeted by H. polygyrus EVs, while neutralization of EV function facilitates parasite expulsion.

Item Type:Articles
Additional Information:This work was supported by a studentship to G.C. from the Biotechnology and Biological Sciences Research Council (BB/J01446X/1), as well as by a fellowship (AHB-097394) and an investigator award (RMM-106122) from the Wellcome Trust, a Wellcome Trust strategic award to the Centre for Immunity, Infection & Evolution at the University of Edinburgh (095831), and core funding from the Wellcome Trust for the Wellcome Centre for Molecular Parasitology (Ref 104111).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Coakley, Miss Gillian and Maizels, Professor Rick
Authors: Coakley, G., McCaskill, J. L., Borger, J. G., Simbari, F., Robertson, E., Millar, M., Harcus, Y., McSorley, H. J., Maizels, R. M., and Buck, A. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cell Reports
Publisher:Elsevier (Cell Press)
ISSN:2211-1247
ISSN (Online):2211-1247
Published Online:23 May 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Cell Reports 19(8): 1545-1557
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
765221Helminths and the Immune System: Regulation, Regulators and ImmunityRichard MaizelsWellcome Trust (WELLCOTR)106122/A/14/ZIII - PARASITOLOGY
371799The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/Z & AIII - PARASITOLOGY