Parasitic helminths secrete extracellular vesicles (EVs) which have potent immunomodulatory effects. Whilst the cargo of EVs has been characterised for many species, we know little about the mechanisms that govern their biogenesis and release. Using antibodies raised against a panel of Fasciola hepatica EV (FhEV) marker proteins, we have identified multiple sites of EV production in the parasite. Discrete immunofluorescence patterns were observed within the gastrodermal cells and tegumental syncytium for different marker proteins whilst the protonephridial (excretory) system and parenchymal-type 2 cells were identified as additional sites of production (or transit) of FhEVs. Ligation was used to mechanically block the oral sucker, excretory pore, or both, to determine the effect on FhEV release from live adult flukes in vitro. This revealed that FhEVs are predominately derived from the gut, whilst the tegument releases EVs to a lesser extent. The data also suggest that the protonephridial system contributes to the small (120 K) EV sub-population. Sphingomyelinase (SMase) activity is a key driver of EV biogenesis in mammalian cells and we have previously identified SMases in FhEVs by mass spectrometry. SMase activity associated with isolated FhEVs was susceptible to the chemical inhibitor GW4869 and treatment of adult flukes with GW4869 led to a significant reduction in 120 K EV release in vitro, suggesting that a ceramide-dependent mechanism could drive 120 K EV formation. In contrast, the release of the larger 15 K EVs was only moderately impacted, indicating that they form independently of SMase activity. Ultrastructural observation of GW4869-treated F. hepatica tissue showed severe disruption to the parenchyma and vacuolation of the tegument, gastrodermal cells and epithelial lining of the excretory ducts. This work establishes that targeted disruption of EV biogenesis and release in helminths is possible, and provides proof-of-concept for future studies investigating EV secretion as a target for parasite control. (C) 2020 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.
机构:
SUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Airola, Michael V.
Shanbhogue, Prajna
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SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Shanbhogue, Prajna
Shamseddine, Achraf A.
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h-index: 0
机构:
SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Shamseddine, Achraf A.
Guja, Kip E.
论文数: 0引用数: 0
h-index: 0
机构:
SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Guja, Kip E.
Senkal, Can E.
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h-index: 0
机构:
SUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Senkal, Can E.
Maini, Rohan
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h-index: 0
机构:
SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Maini, Rohan
Bartke, Nana
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h-index: 0
机构:
Danone Nutricia Res, Singapore 138671, Singapore
Med Univ South Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Bartke, Nana
Wu, Bill X.
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h-index: 0
机构:
Med Univ South Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Wu, Bill X.
Obeid, Lina M.
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h-index: 0
机构:
SUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA
Northport Vet Affairs Med Ctr, Northport, NY 11768 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Obeid, Lina M.
Garcia-Diaz, Miguel
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机构:
SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Garcia-Diaz, Miguel
Hannun, Yusuf A.
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h-index: 0
机构:
SUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USA
SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
机构:
Khon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Biodiscovery & Mol Dev Therapeut, McGregor Rd, Cairns, Qld 4878, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Chaiyadet, Sujittra
Sotillo, Javier
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h-index: 0
机构:
James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Biodiscovery & Mol Dev Therapeut, McGregor Rd, Cairns, Qld 4878, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Sotillo, Javier
Smout, Michael
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h-index: 0
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James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Biodiscovery & Mol Dev Therapeut, McGregor Rd, Cairns, Qld 4878, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Smout, Michael
Cantacessi, Cinzia
论文数: 0引用数: 0
h-index: 0
机构:
James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Biodiscovery & Mol Dev Therapeut, McGregor Rd, Cairns, Qld 4878, Australia
Univ Cambridge, Dept Vet Med, Brisbane, Qld, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Cantacessi, Cinzia
Jones, Malcolm K.
论文数: 0引用数: 0
h-index: 0
机构:
QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia
Univ Queensland, Sch Vet Sci, Gatton, Qld, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
机构:
QIMR Berghofer Med Res Inst, Brisbane, Qld, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Potriquet, Jeremy
Laohaviroj, Marut
论文数: 0引用数: 0
h-index: 0
机构:
Khon Kaen Univ, Fac Med, Dept Pathol, Khon Kaen, ThailandKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Laohaviroj, Marut
Mulvenna, Jason
论文数: 0引用数: 0
h-index: 0
机构:
QIMR Berghofer Med Res Inst, Brisbane, Qld, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Mulvenna, Jason
Brindley, Paul J.
论文数: 0引用数: 0
h-index: 0
机构:
George Washington Univ, Dept Microbiol Immunol & Trop Med, Washington, DC USA
George Washington Univ, Res Ctr Neglected Dis Poverty, Washington, DC USAKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Brindley, Paul J.
Bethony, Jeffrey M.
论文数: 0引用数: 0
h-index: 0
机构:
George Washington Univ, Dept Microbiol Immunol & Trop Med, Washington, DC USA
George Washington Univ, Res Ctr Neglected Dis Poverty, Washington, DC USAKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Bethony, Jeffrey M.
Laha, Thewarach
论文数: 0引用数: 0
h-index: 0
机构:
Khon Kaen Univ, Fac Med, Dept Parasitol, Khon Kaen, ThailandKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Laha, Thewarach
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Sripa, Banchob
Loukas, Alex
论文数: 0引用数: 0
h-index: 0
机构:
James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Biodiscovery & Mol Dev Therapeut, McGregor Rd, Cairns, Qld 4878, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
机构:
SUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Airola, Michael V.
Shanbhogue, Prajna
论文数: 0引用数: 0
h-index: 0
机构:
SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Shanbhogue, Prajna
Shamseddine, Achraf A.
论文数: 0引用数: 0
h-index: 0
机构:
SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Shamseddine, Achraf A.
Guja, Kip E.
论文数: 0引用数: 0
h-index: 0
机构:
SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Guja, Kip E.
Senkal, Can E.
论文数: 0引用数: 0
h-index: 0
机构:
SUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Senkal, Can E.
Maini, Rohan
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h-index: 0
机构:
SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Maini, Rohan
Bartke, Nana
论文数: 0引用数: 0
h-index: 0
机构:
Danone Nutricia Res, Singapore 138671, Singapore
Med Univ South Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Bartke, Nana
Wu, Bill X.
论文数: 0引用数: 0
h-index: 0
机构:
Med Univ South Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Wu, Bill X.
Obeid, Lina M.
论文数: 0引用数: 0
h-index: 0
机构:
SUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USA
Northport Vet Affairs Med Ctr, Northport, NY 11768 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Obeid, Lina M.
Garcia-Diaz, Miguel
论文数: 0引用数: 0
h-index: 0
机构:
SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
Garcia-Diaz, Miguel
Hannun, Yusuf A.
论文数: 0引用数: 0
h-index: 0
机构:
SUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USA
SUNY Stony Brook, Dept Med, Stony Brook, NY 11794 USASUNY Stony Brook, Canc Ctr, Stony Brook, NY 11794 USA
机构:
Khon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Biodiscovery & Mol Dev Therapeut, McGregor Rd, Cairns, Qld 4878, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Chaiyadet, Sujittra
Sotillo, Javier
论文数: 0引用数: 0
h-index: 0
机构:
James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Biodiscovery & Mol Dev Therapeut, McGregor Rd, Cairns, Qld 4878, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Sotillo, Javier
Smout, Michael
论文数: 0引用数: 0
h-index: 0
机构:
James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Biodiscovery & Mol Dev Therapeut, McGregor Rd, Cairns, Qld 4878, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Smout, Michael
Cantacessi, Cinzia
论文数: 0引用数: 0
h-index: 0
机构:
James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Biodiscovery & Mol Dev Therapeut, McGregor Rd, Cairns, Qld 4878, Australia
Univ Cambridge, Dept Vet Med, Brisbane, Qld, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Cantacessi, Cinzia
Jones, Malcolm K.
论文数: 0引用数: 0
h-index: 0
机构:
QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia
Univ Queensland, Sch Vet Sci, Gatton, Qld, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
机构:
QIMR Berghofer Med Res Inst, Brisbane, Qld, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Potriquet, Jeremy
Laohaviroj, Marut
论文数: 0引用数: 0
h-index: 0
机构:
Khon Kaen Univ, Fac Med, Dept Pathol, Khon Kaen, ThailandKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Laohaviroj, Marut
Mulvenna, Jason
论文数: 0引用数: 0
h-index: 0
机构:
QIMR Berghofer Med Res Inst, Brisbane, Qld, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Mulvenna, Jason
Brindley, Paul J.
论文数: 0引用数: 0
h-index: 0
机构:
George Washington Univ, Dept Microbiol Immunol & Trop Med, Washington, DC USA
George Washington Univ, Res Ctr Neglected Dis Poverty, Washington, DC USAKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Brindley, Paul J.
Bethony, Jeffrey M.
论文数: 0引用数: 0
h-index: 0
机构:
George Washington Univ, Dept Microbiol Immunol & Trop Med, Washington, DC USA
George Washington Univ, Res Ctr Neglected Dis Poverty, Washington, DC USAKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Bethony, Jeffrey M.
Laha, Thewarach
论文数: 0引用数: 0
h-index: 0
机构:
Khon Kaen Univ, Fac Med, Dept Parasitol, Khon Kaen, ThailandKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand
Laha, Thewarach
论文数: 引用数:
h-index:
机构:
Sripa, Banchob
Loukas, Alex
论文数: 0引用数: 0
h-index: 0
机构:
James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Biodiscovery & Mol Dev Therapeut, McGregor Rd, Cairns, Qld 4878, AustraliaKhon Kaen Univ, Fac Med, Grad Sch, Biomed Sci, Khon Kaen, Thailand