Extracellular Vesicles from a Helminth Parasite Suppress Macrophage Activation and Constitute an Effective Vaccine for Protective Immunity

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Summary

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.

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Highlights

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EVs from a nematode parasite suppress type 1 and type 2 activation of macrophages
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Antibodies block EV function and increase their co-localization with the lysosome in macrophages
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EV vaccination generates strong antibody responses and protective immunity against infection
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EVs target both the IL-33 pathway and macrophage activation to counter parasite expulsion

Abstract

Coakley et al. find that extracellular vesicles (EVs) from a nematode parasite can suppress host macrophage activation and the alarmin receptor ST2 and that this can be blocked by antibodies. Vaccination with EVs drives strong antibody responses, conferring protection against infection. The authors thus highlight a role for EVs in parasite-host crosstalk.

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Interaction and uptake of exosomes by ovarian cancer cells

Cristina Escrevente, Sascha Keller, Peter Altevogt … (2011)

Background Exosomes consist of membrane vesicles that are secreted by several cell types, including tumors and have been found in biological fluids. Exosomes interact with other cells and may serve as vehicles for the transfer of protein and RNA among cells. Methods SKOV3 exosomes were labelled with carboxyfluoresceine diacetate succinimidyl-ester and collected by ultracentrifugation. Uptake of these vesicles, under different conditions, by the same cells from where they originated was monitored by immunofluorescence microscopy and flow cytometry analysis. Lectin analysis was performed to investigate the glycosylation properties of proteins from exosomes and cellular extracts. Results In this work, the ovarian carcinoma SKOV3 cell line has been shown to internalize exosomes from the same cells via several endocytic pathways that were strongly inhibited at 4°C, indicating their energy dependence. Partial colocalization with the endosome marker EEA1 and inhibition by chlorpromazine suggested the involvement of clathrin-dependent endocytosis. Furthermore, uptake inhibition in the presence of 5-ethyl-N-isopropyl amiloride, cytochalasin D and methyl-beta-cyclodextrin suggested the involvement of additional endocytic pathways. The uptake required proteins from the exosomes and from the cells since it was inhibited after proteinase K treatments. The exosomes were found to be enriched in specific mannose- and sialic acid-containing glycoproteins. Sialic acid removal caused a small but non-significant increase in uptake. Furthermore, the monosaccharides D-galactose, α-L-fucose, α-D-mannose, D-N-acetylglucosamine and the disaccharide β-lactose reduced exosomes uptake to a comparable extent as the control D-glucose. Conclusions In conclusion, exosomes are internalized by ovarian tumor cells via various endocytic pathways and proteins from exosomes and cells are required for uptake. On the other hand, exosomes are enriched in specific glycoproteins that may constitute exosome markers. This work contributes to the knowledge about the properties and dynamics of exosomes in cancer.

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Leishmania exosomes modulate innate and adaptive immune responses through effects on monocytes and dendritic cells.

Yufeng Wang, Joachim Clos, Neil Reiner … (2010)

We investigated the properties of leishmania exosomes with respect to influencing innate and adaptive immune responses. Exosomes from Leishmania donovani modulated human monocyte cytokine responses to IFN-γ in a bimodal fashion by promoting IL-10 production and inhibiting that of TNF-α. Moreover, these vesicles were inhibitory with respect to cytokine responses (IL-12p70, TNF-α, and IL-10) by human monocyte-derived dendritic cells. Exosomes from wild-type (WT) L. donovani failed to prime monocyte-derived dendritic cells to drive the differentiation of naive CD4 T cells into IFN-γ-producing Th1 cells. In contrast, vesicles from heat shock protein (HSP)100(-/-) L. donovani showed a gain-of-function and proinflammatory phenotype and promoted the differentiation of naive CD4 lymphocytes into Th1 cells. Proteomic analysis showed that exosomes from WT and HSP100(-/-) leishmania had distinct protein cargo, suggesting that packaging of proteins into exosomes is dependent in part on HSP100. Treatment of C57BL/6 mice with WT L. donovani exosomes prior to challenge with WT organisms exacerbated infection and promoted IL-10 production in the spleen. In contrast, HSP100(-/-) exosomes promoted spleen cell production of IFN-γ and did not adversely affect hepatic parasite burdens. Furthermore, the proparasitic properties of WT exosomes were not species specific because BALB/c mice exposed to Leishmania major exosomes showed increased Th2 polarization and exacerbation of disease in response to infection with L. major. These findings demonstrate that leishmania exosomes are predominantly immunosuppressive. Moreover, to our knowledge, this is the first evidence to suggest that changes in the protein cargo of exosomes may influence the impact of these vesicles on myeloid cell function.

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T1/St2-Deficient Mice Demonstrate the Importance of T1/St2 in Developing Primary T Helper Cell Type 2 Responses

Michael J Townsend, Padraic Fallon, David Matthews … (2000)

We have generated mice with a deficiency in T1/ST2 expression to clarify the roles of T1/ST2 in T helper cell type 2 (Th2) responses. Using immunological challenges normally characterized by a Th2-like response, we have compared the responses of T1/ST2-deficient mice with those generated by wild-type mice. Using a primary pulmonary granuloma model, induced with Schistosoma mansoni eggs, we demonstrate that granuloma formation, characterized by eosinophil infiltration, is abrogated in T1/ST2-deficient mice. Furthermore, we clearly demonstrate that in the absence of T1/ST2 expression, the levels of Th2 cytokine production are severely impaired after immunization. Thus, in a secondary pulmonary granuloma model, draining lymph node cells from the T1/ST2-deficient animals produced significantly reduced levels of IL-4 and IL-5, despite developing granulomas of a magnitude similar to those of wild-type mice and comparable antigen-specific immunoglobulin isotype production. These data clearly demonstrate that T1/ST2 expression plays a role in the development of Th2-like cytokine responses and indicate that effector functions are inhibited in its absence.

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Author and article information

Contributors

Rick M. Maizels

Amy H. Buck

Journal

Journal ID (nlm-ta): Cell Rep

Journal ID (iso-abbrev): Cell Rep

Title: Cell Reports

Publisher: Cell Press

ISSN (Electronic): 2211-1247

Publication date PMC-release: 23 May 2017

Publication date Collection: 23 May 2017

Publication date (Electronic): 23 May 2017

Volume: 19

Issue: 8

Pages: 1545-1557

Affiliations

[1 ]Institute of Immunology and Infection Research and Centre for Immunity, Infection & Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK

[2 ]Centre for Inflammation Research, University of Edinburgh, The Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

[3 ]Wellcome Centre for Molecular Parasitology, Institute for Infection, Immunity and Inflammation, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8TA, UK

Author notes

[∗ ]Corresponding author rick.maizels@ 123456glasgow.ac.uk

[∗∗ ]Corresponding author a.buck@ 123456ed.ac.uk

[4]

Present address: Monash University, Alfred Medical Research and Education Precinct, Level 6 Burnet Tower, 89 Commercial Road, Melbourne, VIC 3004, Australia

[5]

Present address: Centre for Cardiovascular Research, University of Edinburgh, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

[6]

Senior author

[7]

Lead Contact

Article

Publisher ID: S2211-1247(17)30606-X

DOI: 10.1016/j.celrep.2017.05.001

PMC ID: 5457486

PubMed ID: 28538175

SO-VID: 2b20022e-e1fb-4e22-bd74-a1aa5c84b14c

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

History

Date received : 27 October 2016

Date revision received : 30 March 2017

Date accepted : 27 April 2017

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Extracellular Vesicles from a Helminth Parasite Suppress Macrophage Activation and Constitute an Effective Vaccine for Protective Immunity

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Bacterial extracellular vesicles

Most cited references 35

Interaction and uptake of exosomes by ovarian cancer cells

Leishmania exosomes modulate innate and adaptive immune responses through effects on monocytes and dendritic cells.

T1/St2-Deficient Mice Demonstrate the Importance of T1/St2 in Developing Primary T Helper Cell Type 2 Responses

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Cited by 97

Most referenced authors 708