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Maizels RM, McSorley HJ, Smits HH, Ten Dijke P, Hinck AP. Cytokines from parasites: manipulating host responses by molecular mimicry. Biochem J 2025; 482:BCJ20253061. [PMID: 40302223 DOI: 10.1042/bcj20253061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 04/01/2025] [Indexed: 05/02/2025]
Abstract
Helminth parasites have evolved sophisticated methods for manipulating the host immune response to ensure long-term survival in their chosen niche, for example, by secreting products that interfere with the host cytokine network. Studies on the secretions of Heligmosomoides polygyrus have identified a family of transforming growth factor-β (TGF-β) mimics (TGMs), which bear no primary amino acid sequence similarity to mammalian TGF-β, but functionally replicate or antagonise TGF-β effects in restricted cell types. The prototypic member, TGM1, induces in vitro differentiation of Foxp3+ T regulatory cells and attenuates airway allergic and intestinal inflammation in animal models. TGM1 is one of a family of ten TGM proteins expressed by H. polygyrus. It is a five-domain modular protein in which domains 1-2 bind TGFBR1, and domain 3 binds TGFBR2; domains 4-5 increase its potency by binding a co-receptor, CD44, highly expressed on immune cells. Domains 4-5 are more diverse in other TGMs, which bind co-receptors on cells such as fibroblasts. One variant, TGM6, lacks domains 1-2 and hence cannot transduce a signal but binds TGFBR2 through domain 3 and a co-receptor expressed on fibroblasts through domains 4-5 and blocks TGF-β signalling in fibroblasts and epithelial cells; T cells do not express the co-receptor and are not inhibited by TGM6. Hence, different family members have evolved to act as agonists or antagonists on various cell types. TGMs, which function by molecularly mimicking binding of the host cytokine to the host TGF-β receptors, are examples of highly evolved immunomodulators from parasites, including those that block interleukin (IL)-13 and IL-33 signalling, modulate macrophage and dendritic cell responses and modify host cell metabolism. The emerging panoply and potency of helminth evasion molecules illustrates the range of strategies in play to maintain long-term infections in the mammalian host.
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Affiliation(s)
- Rick M Maizels
- School of Infection and Immunity, University of Glasgow, Glasgow, U.K
| | - Henry J McSorley
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, U.K
| | - Hermelijn H Smits
- Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
| | - Peter Ten Dijke
- Oncode Institute and Department of Cell and Chemical Biology, University of Leiden, Leiden, Netherlands
| | - Andrew P Hinck
- Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh PA 15260, U.S.A
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Colomb F, McSorley HJ. Protein families secreted by nematodes to modulate host immunity. Curr Opin Microbiol 2025; 84:102582. [PMID: 39954371 DOI: 10.1016/j.mib.2025.102582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 01/14/2025] [Accepted: 01/24/2025] [Indexed: 02/17/2025]
Abstract
Parasitic nematodes release a wide variety of immunomodulatory proteins, which allow them to escape the host's immune-mediated killing or ejection mechanisms. This immunomodulation is mediated by nematode excretory/secretory (E/S) products, which contain multiple families of immunomodulatory proteins. Many of these families are conserved across different parasitic nematodes, while others are apparently unique to specific species. While some E/S products interact with host proteins, others have evolved to target host lipids, glycans, and metabolites. In this review, we will focus on three families of immunomodulatory proteins, which are particularly expanded in intestinal nematodes: the venom allergen-like proteins, the apyrases, and the complement control protein domain-containing proteins. These families of proteins suppress host immune responses, and evidence is gathering that these could be effective vaccine antigens against these intractable parasites.
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Affiliation(s)
- Florent Colomb
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland
| | - Henry J McSorley
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.
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3
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Maizels RM, Newfeld SJ. Convergent Evolution in a Murine Intestinal Parasite Rapidly Created the TGM Family of Molecular Mimics to Suppress the Host Immune Response. Genome Biol Evol 2023; 15:evad158. [PMID: 37625791 PMCID: PMC10516467 DOI: 10.1093/gbe/evad158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 08/27/2023] Open
Abstract
The Transforming Growth Factor-β mimic (TGM) multigene family was recently discovered in the murine intestinal parasite Heligmosomoides polygyrus. This family was shaped by an atypical set of organismal and molecular evolutionary mechanisms along its path through the adaptive landscape. The relevant mechanisms are mimicry, convergence, exon modularity, new gene origination, and gene family neofunctionalization. We begin this review with a description of the TGM family and then address two evolutionary questions: "Why were TGM proteins needed for parasite survival" and "when did the TGM family originate"? For the former, we provide a likely answer, and for the latter, we identify multiple TGM building blocks in the ruminant intestinal parasite Haemonchus contortus. We close by identifying avenues for future investigation: new biochemical data to assign functions to more family members as well as new sequenced genomes in the Trichostrongyloidea superfamily and the Heligmosomoides genus to clarify TGM origins and expansion. Continued study of TGM proteins will generate increased knowledge of Transforming Growth Factor-β signaling, host-parasite interactions, and metazoan evolutionary mechanisms.
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Affiliation(s)
- Rick M Maizels
- Wellcome Centre for Integrative Parasitology, School of Infection and Immunity, University of Glasgow, Glasgow, United Kingdom
| | - Stuart J Newfeld
- School of Life Sciences, Arizona State University, Tempe, Arizona, USA
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Lo WS, Roca M, Dardiry M, Mackie M, Eberhardt G, Witte H, Hong R, Sommer RJ, Lightfoot JW. Evolution and Diversity of TGF-β Pathways are Linked with Novel Developmental and Behavioral Traits. Mol Biol Evol 2022; 39:msac252. [PMID: 36469861 PMCID: PMC9733428 DOI: 10.1093/molbev/msac252] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 10/19/2022] [Accepted: 11/07/2022] [Indexed: 12/12/2022] Open
Abstract
Transforming growth factor-β (TGF-β) signaling is essential for numerous biologic functions. It is a highly conserved pathway found in all metazoans including the nematode Caenorhabditis elegans, which has also been pivotal in identifying many components. Utilizing a comparative evolutionary approach, we explored TGF-β signaling in nine nematode species and revealed striking variability in TGF-β gene frequency across the lineage. Of the species analyzed, gene duplications in the DAF-7 pathway appear common with the greatest disparity observed in Pristionchus pacificus. Specifically, multiple paralogues of daf-3, daf-4 and daf-7 were detected. To investigate this additional diversity, we induced mutations in 22 TGF-β components and generated corresponding double, triple, and quadruple mutants revealing both conservation and diversification in function. Although the DBL-1 pathway regulating body morphology appears highly conserved, the DAF-7 pathway exhibits functional divergence, notably in some aspects of dauer formation. Furthermore, the formation of the phenotypically plastic mouth in P. pacificus is partially influenced through TGF-β with the strongest effect in Ppa-tag-68. This appears important for numerous processes in P. pacificus but has no known function in C. elegans. Finally, we observe behavioral differences in TGF-β mutants including in chemosensation and the establishment of the P. pacificus kin-recognition signal. Thus, TGF-β signaling in nematodes represents a stochastic genetic network capable of generating novel functions through the duplication and deletion of associated genes.
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Affiliation(s)
- Wen-Sui Lo
- Department for Integrative Evolutionary Biology, Max-Planck Institute for Biology Tübingen, Max-Planck Ring 9, 72076 Tübingen, Germany
| | - Marianne Roca
- Max Planck Research Group Genetics of Behavior, Max Planck Institute for Neurobiology of Behavior—Caesar, Ludwig-Erhard-Allee 2, 53175, Bonn, Germany
| | - Mohannad Dardiry
- Department for Integrative Evolutionary Biology, Max-Planck Institute for Biology Tübingen, Max-Planck Ring 9, 72076 Tübingen, Germany
| | - Marisa Mackie
- Department of Biology, California State University, Northridge, CA
| | - Gabi Eberhardt
- Department for Integrative Evolutionary Biology, Max-Planck Institute for Biology Tübingen, Max-Planck Ring 9, 72076 Tübingen, Germany
| | - Hanh Witte
- Department for Integrative Evolutionary Biology, Max-Planck Institute for Biology Tübingen, Max-Planck Ring 9, 72076 Tübingen, Germany
| | - Ray Hong
- Department of Biology, California State University, Northridge, CA
| | - Ralf J Sommer
- Department for Integrative Evolutionary Biology, Max-Planck Institute for Biology Tübingen, Max-Planck Ring 9, 72076 Tübingen, Germany
| | - James W Lightfoot
- Max Planck Research Group Genetics of Behavior, Max Planck Institute for Neurobiology of Behavior—Caesar, Ludwig-Erhard-Allee 2, 53175, Bonn, Germany
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Maruszewska-Cheruiyot M, Stear MJ, Machcińska M, Donskow-Łysoniewska K. Importance of TGFβ in Cancer and Nematode Infection and Their Interaction-Opinion. Biomolecules 2022; 12:1572. [PMID: 36358922 PMCID: PMC9687433 DOI: 10.3390/biom12111572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/20/2022] [Accepted: 10/24/2022] [Indexed: 09/29/2023] Open
Abstract
Historically, there has been little interaction between parasitologists and oncologists, although some helminth infections predispose to the development of tumours. In addition, both parasites and tumours need to survive immune attack. Recent research suggests that both tumours and parasites suppress the immune response to increase their chances of survival. They both co-opt the transforming growth factor beta (TGFβ) signalling pathway to modulate the immune response to their benefit. In particular, there is concern that suppression of the immune response by nematodes and their products could enhance susceptibility to tumours in both natural and artificial infections.
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Affiliation(s)
| | - Michael James Stear
- Department of Animal, Plant and Soil Science, Agribio, La Trobe University, Bundoora 3086, Australia
| | - Maja Machcińska
- Department of Experimental Immunotherapy, Faculty of Medicine, Lazarski University, 02-662 Warsaw, Poland
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Lok JB, Kliewer SA, Mangelsdorf DJ. The 'nuclear option' revisited: Confirmation of Ss-daf-12 function and therapeutic potential in Strongyloides stercoralis and other parasitic nematode infections. Mol Biochem Parasitol 2022; 250:111490. [PMID: 35697206 DOI: 10.1016/j.molbiopara.2022.111490] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 05/19/2022] [Accepted: 06/07/2022] [Indexed: 10/18/2022]
Abstract
Mechanisms governing morphogenesis and development of infectious third-stage larvae (L3i) of parasitic nematodes have been likened to those regulating dauer development in Caenorhabditis elegans. Dauer regulatory signal transduction comprises initial G protein-coupled receptor (GPCR) signaling in chemosensory neurons of the amphidial complex that regulates parallel insulin- and TGFβ-like signaling in the tissues. Insulin- and TGFβ-like signals converge to co-regulate steroid signaling through the nuclear receptor (NR) DAF-12. Discovery of the steroid ligands of DAF-12 opened a new avenue of small molecule physiology in C. elegans. These signaling pathways are conserved in parasitic nematodes and an increasing body of evidence supports their function in formation and developmental regulation of L3i during the infectious process in soil transmitted species. This review presents these lines of evidence for G protein-coupled receptor (GPCR), insulin- and TGFβ-like signaling in brief and focuses primarily on signaling through parasite orthologs of DAF-12. We discuss in some depth the deployment of sensitive analytical techniques to identify Δ7-dafachronic acid as the natural ligand of DAF-12 homologs in Strongyloides stercoralis and Haemonchus contortus and of targeted mutagenesis by CRISPR/Cas9 to assign dauer-like regulatory function to the NR Ss-DAF-12, its coactivator Ss-DIP-1 and the key ligand biosynthetic enzyme Ss-CYP-22a9. Finally, we present published evidence of the potential of Ss-DAF-12 signaling as a chemotherapeutic target in human strongyloidiasis.
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Affiliation(s)
- James B Lok
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA, USA.
| | - Steven A Kliewer
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - David J Mangelsdorf
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX USA
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Hildersley KA, McNeilly TN, Gillan V, Otto TD, Löser S, Gerbe F, Jay P, Maizels RM, Devaney E, Britton C. Tuft Cells Increase Following Ovine Intestinal Parasite Infections and Define Evolutionarily Conserved and Divergent Responses. Front Immunol 2021; 12:781108. [PMID: 34880874 PMCID: PMC8646091 DOI: 10.3389/fimmu.2021.781108] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/05/2021] [Indexed: 01/03/2023] Open
Abstract
Helminth parasite infections of humans and livestock are a global health and economic problem. Resistance of helminths to current drug treatment is an increasing problem and alternative control approaches, including vaccines, are needed. Effective vaccine design requires knowledge of host immune mechanisms and how these are stimulated. Mouse models of helminth infection indicate that tuft cells, an unusual type of epithelial cell, may 'sense' infection in the small intestine and trigger a type 2 immune response. Currently nothing is known of tuft cells in immunity in other host species and in other compartments of the gastrointestinal (GI) tract. Here we address this gap and use immunohistochemistry and single cell RNA-sequencing to detail the presence and gene expression profile of tuft cells in sheep following nematode infections. We identify and characterize tuft cells in the ovine abomasum (true stomach of ruminants) and show that they increase significantly in number following infection with the globally important nematodes Teladorsagia circumcincta and Haemonchus contortus. Ovine abomasal tuft cells show enriched expression of tuft cell markers POU2F3, GFI1B, TRPM5 and genes involved in signaling and inflammatory pathways. However succinate receptor SUCNR1 and free fatty acid receptor FFAR3, proposed as 'sensing' receptors in murine tuft cells, are not expressed, and instead ovine tuft cells are enriched for taste receptor TAS2R16 and mechanosensory receptor ADGRG6. We also identify tuft cell sub-clusters at potentially different stages of maturation, suggesting a dynamic process not apparent from mouse models of infection. Our findings reveal a tuft cell response to economically important parasite infections and show that while tuft cell effector functions have been retained during mammalian evolution, receptor specificity has diverged. Our data advance knowledge of host-parasite interactions in the GI mucosa and identify receptors that may potentiate type 2 immunity for optimized control of parasitic nematodes.
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Affiliation(s)
- Katie A. Hildersley
- Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom
- Disease Control Department, Moredun Research Institute, Penicuik, United Kingdom
| | - Tom N. McNeilly
- Disease Control Department, Moredun Research Institute, Penicuik, United Kingdom
| | - Victoria Gillan
- Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom
| | - Thomas D. Otto
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Stephan Löser
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - François Gerbe
- Institut de Genomique Fonctionnelle (IGF), University of Montpellier, CNRS, INSERM, Montpellier, France
| | - Philippe Jay
- Institut de Genomique Fonctionnelle (IGF), University of Montpellier, CNRS, INSERM, Montpellier, France
| | - Rick M. Maizels
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Eileen Devaney
- Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom
| | - Collette Britton
- Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom
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A journey through 50 years of research relevant to the control of gastrointestinal nematodes in ruminant livestock and thoughts on future directions. Int J Parasitol 2021; 51:1133-1151. [PMID: 34774857 DOI: 10.1016/j.ijpara.2021.10.007] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 11/20/2022]
Abstract
This review article provides an historical perspective on some of the major research advances of relevance to ruminant livestock gastrointestinal nematode control over the last 50 years. Over this period, gastrointestinal nematode control has been dominated by the use of broad-spectrum anthelmintic drugs. Whilst this has provided unprecedented levels of successful control for many years, this approach has been gradually breaking down for more than two decades and is increasingly unsustainable which is due, at least in part, to the emergence of anthelmintic drug resistance and a number of other factors discussed in this article. We first cover the remarkable success story of the discovery and development of broad-spectrum anthelmintic drugs, the changing face of anthelmintic drug discovery research and the emergence of anthelmintic resistance. This is followed by a review of some of the major advances in the increasingly important area of non-pharmaceutical gastrointestinal nematode control including immunology and vaccine development, epidemiological modelling and some of the alternative control strategies such as breeding for host resistance, refugia-based methods and biological control. The last 50 years have witnessed remarkable innovation and success in research aiming to improve ruminant livestock gastrointestinal nematode control, particularly given the relatively small size of the research community and limited funding. In spite of this, the growing global demand for livestock products, together with the need to maximise production efficiencies, reduce environmental impacts and safeguard animal welfare - as well as specific challenges such as anthelmintic drug resistance and climate change- mean that gastrointestinal nematode researchers will need to be as innovative in the next 50 years as in the last.
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Vlaar LE, Bertran A, Rahimi M, Dong L, Kammenga JE, Helder J, Goverse A, Bouwmeester HJ. On the role of dauer in the adaptation of nematodes to a parasitic lifestyle. Parasit Vectors 2021; 14:554. [PMID: 34706780 PMCID: PMC8555053 DOI: 10.1186/s13071-021-04953-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 08/13/2021] [Indexed: 11/25/2022] Open
Abstract
Nematodes are presumably the most abundant Metazoa on Earth, and can even be found in some of the most hostile environments of our planet. Various types of hypobiosis evolved to adapt their life cycles to such harsh environmental conditions. The five most distal major clades of the phylum Nematoda (Clades 8-12), formerly referred to as the Secernentea, contain many economically relevant parasitic nematodes. In this group, a special type of hypobiosis, dauer, has evolved. The dauer signalling pathway, which culminates in the biosynthesis of dafachronic acid (DA), is intensively studied in the free-living nematode Caenorhabditis elegans, and it has been hypothesized that the dauer stage may have been a prerequisite for the evolution of a wide range of parasitic lifestyles among other nematode species. Biosynthesis of DA is not specific for hypobiosis, but if it results in exit of the hypobiotic state, it is one of the main criteria to define certain behaviour as dauer. Within Clades 9 and 10, the involvement of DA has been validated experimentally, and dauer is therefore generally accepted to occur in those clades. However, for other clades, such as Clade 12, this has hardly been explored. In this review, we provide clarity on the nomenclature associated with hypobiosis and dauer across different nematological subfields. We discuss evidence for dauer-like stages in Clades 8 to 12 and support this with a meta-analysis of available genomic data. Furthermore, we discuss indications for a simplified dauer signalling pathway in parasitic nematodes. Finally, we zoom in on the host cues that induce exit from the hypobiotic stage and introduce two hypotheses on how these signals might feed into the dauer signalling pathway for plant-parasitic nematodes. With this work, we contribute to the deeper understanding of the molecular mechanisms underlying hypobiosis in parasitic nematodes. Based on this, novel strategies for the control of parasitic nematodes can be developed.
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Affiliation(s)
- Lieke E Vlaar
- Plant Hormone Biology Group, Green Life Sciences Cluster, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Andre Bertran
- Laboratory of Nematology, Department of Plant Sciences, Wageningen University, 6708 PB, Wageningen, The Netherlands
| | - Mehran Rahimi
- Plant Hormone Biology Group, Green Life Sciences Cluster, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Lemeng Dong
- Plant Hormone Biology Group, Green Life Sciences Cluster, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands
| | - Jan E Kammenga
- Laboratory of Nematology, Department of Plant Sciences, Wageningen University, 6708 PB, Wageningen, The Netherlands
| | - Johannes Helder
- Laboratory of Nematology, Department of Plant Sciences, Wageningen University, 6708 PB, Wageningen, The Netherlands
| | - Aska Goverse
- Laboratory of Nematology, Department of Plant Sciences, Wageningen University, 6708 PB, Wageningen, The Netherlands
| | - Harro J Bouwmeester
- Plant Hormone Biology Group, Green Life Sciences Cluster, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands.
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Abstract
Transforming Growth Factor-β is a potent regulator of the immune system, acting at every stage from thymic differentiation, population of the periphery, control of responsiveness, tissue repair and generation of memory. It is therefore a central player in the immune response to infectious pathogens, but its contribution is often clouded by multiple roles acting on different cells in time and space. Hence, context is all-important in understanding when TGF-β is beneficial or detrimental to the outcome of infection. In this review, a full range of infectious agents from viruses to helminth parasites are explored within this framework, drawing contrasts and general conclusions about the importance of TGF-β in these diseases.
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Affiliation(s)
- Rick M Maizels
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
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11
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Bobardt SD, Dillman AR, Nair MG. The Two Faces of Nematode Infection: Virulence and Immunomodulatory Molecules From Nematode Parasites of Mammals, Insects and Plants. Front Microbiol 2020; 11:577846. [PMID: 33343521 PMCID: PMC7738434 DOI: 10.3389/fmicb.2020.577846] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 11/02/2020] [Indexed: 12/20/2022] Open
Abstract
Helminths stage a powerful infection that allows the parasite to damage host tissue through migration and feeding while simultaneously evading the host immune system. This feat is accomplished in part through the release of a diverse set of molecules that contribute to pathogenicity and immune suppression. Many of these molecules have been characterized in terms of their ability to influence the infectious capabilities of helminths across the tree of life. These include nematodes that infect insects, known as entomopathogenic nematodes (EPN) and plants with applications in agriculture and medicine. In this review we will first discuss the nematode virulence factors, which aid parasite colonization or tissue invasion, and cause many of the negative symptoms associated with infection. These include enzymes involved in detoxification, factors essential for parasite development and growth, and highly immunogenic ES proteins. We also explore how these parasites use several classes of molecules (proteins, carbohydrates, and nucleic acids) to evade the host's immune defenses. For example, helminths release immunomodulatory molecules in extracellular vesicles that may be protective in allergy and inflammatory disease. Collectively, these nematode-derived molecules allow parasites to persist for months or even years in a host, avoiding being killed or expelled by the immune system. Here, we evaluate these molecules, for their individual and combined potential as vaccine candidates, targets for anthelminthic drugs, and therapeutics for allergy and inflammatory disease. Last, we evaluate shared virulence and immunomodulatory mechanisms between mammalian and non-mammalian plant parasitic nematodes and EPNs, and discuss the utility of EPNs as a cost-effective model for studying nematode-derived molecules. Better knowledge of the virulence and immunomodulatory molecules from both entomopathogenic nematodes and soil-based helminths will allow for their use as beneficial agents in fighting disease and pests, divorced from their pathogenic consequences.
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Affiliation(s)
- Sarah D. Bobardt
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Adler R. Dillman
- Department of Nematology, University of California, Riverside, Riverside, CA, United States
| | - Meera G. Nair
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
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12
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He L, Liu H, Zhang BY, Li FF, Di WD, Wang CQ, Zhou CX, Liu L, Li TT, Zhang T, Fang R, Hu M. A daf-7-related TGF-β ligand (Hc-tgh-2) shows important regulations on the development of Haemonchus contortus. Parasit Vectors 2020; 13:326. [PMID: 32586367 PMCID: PMC7318536 DOI: 10.1186/s13071-020-04196-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 06/17/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND In most multicellular organisms, the transforming growth factor-β (TGF-β) signalling pathway is involved in regulating the growth and stem cell differentiation. Previous studies have demonstrated the importance of three key molecules in this pathway in the parasitic nematode Haemonchus contortus, including one TGF-β type I receptor (Hc-tgfbr1), one TGF-β type II receptor (Hc-tgfbr2), and one co-Smad (Hc-daf-3), which regulated the developmental transition from the free-living to the parasitic stages of this parasite. However, almost nothing is known about the function of the TGF-β ligand (Hc-tgh-2) of H. contortus. METHODS Here, the temporal transcription profiles of Hc-tgh-2 at eight different developmental stages and spatial expression patterns of Hc-TGH-2 in adult female and male worms of H. contortus have been examined by real-time PCR and immunohistochemistry, respectively. In addition, RNA interference (RNAi) by soaking was employed to assess the importance of Hc-tgh-2 in the development from exsheathed third-stage larvae (xL3s) to fourth-stage larvae (L4s) in H. contortus. RESULTS Hc-tgh-2 was continuously transcribed in all eight developmental stages of H. contortus studied with the highest level in the infective third-stage larvae (iL3) and Hc-TGH-2 was located in the muscle of the body wall, intestine, ovary of adult females and testes of adult males. Silencing Hc-tgh-2 by the specific double-stranded RNA (dsRNA), decreased the transcript level of Hc-tgh-2 and resulted in fewer xL3s developing to L4s in vitro. CONCLUSIONS These results suggested that the TGF-β ligand, Hc-TGH-2, could play important roles in the developmental transition from the free-living (L3s) to the parasitic stage (L4s). Furthermore, it may also take part in the processes such as digestion, absorption, host immune response and reproductive development in H. contortus adults.
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Affiliation(s)
- Li He
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Hui Liu
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Bi-Ying Zhang
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Fang-Fang Li
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Wen-Da Di
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Chun-Qun Wang
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Cai-Xian Zhou
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Lu Liu
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Ting-Ting Li
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Ting Zhang
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Rui Fang
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Min Hu
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China.
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The potential for vaccines against scour worms of small ruminants. Int J Parasitol 2020; 50:533-553. [PMID: 32569640 DOI: 10.1016/j.ijpara.2020.04.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 04/01/2020] [Accepted: 04/03/2020] [Indexed: 02/08/2023]
Abstract
This review addresses the research landscape regarding vaccines against scour worms, particularly Trichostrongylus spp. and Teladorsagia circumcincta. The inability of past research to deliver scour-worm vaccines with reliable and reproducible efficacy has been due in part to gaps in knowledge concerning: (i) host-parasite interactions leading to development of type-2 immunity, (ii) definition of an optimal suite of parasite antigens, and (iii) rational formulation and administration to induce protective immunity against gastrointestinal nematodes (GIN) at the site of infestation. Recent 'omics' developments enable more systematic analyses. GIN genomes are reaching completion, facilitating "reverse vaccinology" approaches that have been used successfully for the Rhipicephalus australis vaccine for cattle tick, while methods for gene silencing and editing in GIN enable identification and validation of potential vaccine antigens. We envisage that any efficacious scour worm vaccine(s) would be adopted similarly to "Barbervax™" within integrated parasite management schemes. Vaccines would therefore effectively parallel the use of resistant animals, and reduce the frequency of drenching and pasture contamination. These aspects of integration, efficacy and operation require updated models and validation in the field. The conclusion of this review outlines an approach to facilitate an integrated research program.
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Li FF, Gasser RB, Liu F, Shan JN, Di WD, He L, Zhou CX, Wang CQ, Fang R, Hu M. Identification and characterization of an R-Smad homologue (Hco-DAF-8) from Haemonchus contortus. Parasit Vectors 2020; 13:164. [PMID: 32245505 PMCID: PMC7119156 DOI: 10.1186/s13071-020-04034-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 03/25/2020] [Indexed: 01/18/2023] Open
Abstract
Background Smad proteins are essential cellular mediators within the transforming growth factor-β (TGF-β) superfamily. They directly transmit incoming signals from the cell surface receptors to the nucleus. In spite of their functional importance, almost nothing is known about Smad proteins in parasitic nematodes including Haemonchus contortus, an important blood-sucking nematode of small ruminants. Methods Based on genomic and transcriptome data for H. contortus and using bioinformatics methods, a Smad homologue (called Hco-daf-8) was inferred from H. contortus and the structural characteristics of this gene and its encoded protein Hco-DAF-8 established. Using real-time PCR and immunofluorescence assays, temporal transcriptional and spatial expression profiles of Hco-daf-8 were studied. Gene rescue in Caenorhabditis elegans was then applied to assess the function of Hco-daf-8 and a specific inhibitor of human Smad3 (called SIS3) was employed to evaluate the roles of Hco-DAF-8 in H. contortus development. Results The features of Hco-DAF-8 (502 amino acids), including conserved R-Smad domains and residues of the L3-loop that determine pathway specificity, are consistent with a TGF-β type I receptor-activated R-Smad. The Hco-daf-8 gene was transcribed in all developmental stages of H. contortus studied, with a higher level of transcription in the fourth-stage larval (L4) females and the highest level in adult males. Hco-DAF-8 was expressed in the platymyarian muscular cells, intestine and reproductive system of adult stages. Gene rescue experiments showed that Hco-daf-8 was able to partially rescue gene function in a daf-8 deficient mutant strain of C. elegans, leading to a resumption of normal development. In H. contortus, SIS3 was shown to affect H. contortus development from the exsheathed third-stage larvae (L3s) to L4s in vitro. Conclusions These findings suggest that Hco-DAF-8, encoded by the gene Hco-daf-8, is an important cellular mediator of H. contortus development via the TGF-β signalling pathway. They provide a basis for future explorations of Hco-DAF-8 and associated pathways in H. contortus and other important parasitic nematodes.![]()
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Affiliation(s)
- Fang-Fang Li
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Robin B Gasser
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China.,Melbourne Veterinary School, Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Feng Liu
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Jia-Nan Shan
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Wen-Da Di
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Li He
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Cai-Xian Zhou
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Chun-Qun Wang
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Rui Fang
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China
| | - Min Hu
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, Hubei, China.
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Elucidating the molecular and developmental biology of parasitic nematodes: Moving to a multiomics paradigm. ADVANCES IN PARASITOLOGY 2020; 108:175-229. [PMID: 32291085 DOI: 10.1016/bs.apar.2019.12.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In the past two decades, significant progress has been made in the sequencing, assembly, annotation and analyses of genomes and transcriptomes of parasitic worms of socioeconomic importance. This progress has somewhat improved our knowledge and understanding of these pathogens at the molecular level. However, compared with the free-living nematode Caenorhabditis elegans, the areas of functional genomics, transcriptomics, proteomics and metabolomics of parasitic nematodes are still in their infancy, and there are major gaps in our knowledge and understanding of the molecular biology of parasitic nematodes. The information on signalling molecules, molecular pathways and microRNAs (miRNAs) that are known to be involved in developmental processes in C. elegans and the availability of some molecular resources (draft genomes, transcriptomes and some proteomes) for selected parasitic nematodes provide a basis to start exploring the developmental biology of parasitic nematodes. Indeed, some studies have identified molecules and pathways that might associate with developmental processes in related, parasitic nematodes, such as Haemonchus contortus (barber's pole worm). However, detailed information is often scant and 'omics resources are limited, preventing a proper integration of 'omic data sets and comprehensive analyses. Moreover, little is known about the functional roles of pheromones, hormones, signalling pathways and post-transcriptional/post-translational regulations in the development of key parasitic nematodes throughout their entire life cycles. Although C. elegans is an excellent model to assist molecular studies of parasitic nematodes, its use is limited when it comes to explorations of processes that are specific to parasitism within host animals. A deep understanding of parasitic nematodes, such as H. contortus, requires substantially enhanced resources and the use of integrative 'omics approaches for analyses. The improved genome and well-established in vitro larval culture system for H. contortus provide unprecedented opportunities for comprehensive studies of the transcriptomes (mRNA and miRNA), proteomes (somatic, excretory/secretory and phosphorylated proteins) and lipidomes (e.g., polar and neutral lipids) of this nematode. Such resources should enable in-depth explorations of its developmental biology at a level, not previously possible. The main aims of this review are (i) to provide a background on the development of nematodes, with a particular emphasis on the molecular aspects involved in the dauer formation and exit in C. elegans; (ii) to critically appraise the current state of knowledge of the developmental biology of parasitic nematodes and identify key knowledge gaps; (iii) to cover salient aspects of H. contortus, with a focus on the recent advances in genomics, transcriptomics, proteomics and lipidomics as well as in vitro culturing systems; (iv) to review recent advances in our knowledge and understanding of the molecular and developmental biology of H. contortus using an integrative multiomics approach, and discuss the implications of this approach for detailed explorations of signalling molecules, molecular processes and pathways likely associated with nematode development, adaptation and parasitism, and for the identification of novel intervention targets against these pathogens. Clearly, the multiomics approach established recently is readily applicable to exploring a wide range of interesting and socioeconomically significant parasitic worms (including also trematodes and cestodes) at the molecular level, and to elucidate host-parasite interactions and disease processes.
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A DAF-3 co-Smad molecule functions in Haemonchus contortus development. Parasit Vectors 2019; 12:609. [PMID: 31881930 PMCID: PMC6935219 DOI: 10.1186/s13071-019-3855-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 12/16/2019] [Indexed: 11/10/2022] Open
Abstract
Background The Smad proteins function in TGF-β signalling transduction. In the model nematode Caenorhabditis elegans, the co-Smad, DAF-3 mediates R-Smads and performs a central role in DAF-7 signal transduction, regulating dauer formation and reproductive processes. Considering the divergent evolutionary patterns of the DAF-7 signalling pathway in parasitic nematodes, it is meaningful to explore the structure and function of DAF-3 in parasitic nematodes, such as Haemonchus contortus. Methods A daf-3 gene (Hc-daf-3) and its predicted product (Hc-DAF-3) were identified from H. contortus and characterised using integrated genomic and genetic approaches. In addition to immunohistochemistry employed to localise Hc-DAF-3 within adult worm sections, real-time PCR was conducted to assess the transcriptional profiles in different developmental stages of H. contortus and RNA interference (RNAi) was performed in vitro to assess the functional importance of Hc-daf-3 in the development of H. contortus. Results Hc-DAF-3 sequences predicted from Hc-daf-3 displayed typical features of the co-Smad subfamily. The native Hc-DAF-3 was localised to the gonad and cuticle of adult parasites. In addition, Hc-daf-3 was transcribed in all developmental stages studied, with a higher level in the third-stage larvae (L3) and adult females. Moreover, silencing Hc-daf-3 by RNAi retarded L4 development. Conclusion The findings of the present study demonstrated an important role of Hc-DAF-3 in the development of H. contortus larvae.
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He L, Gasser RB, Li T, Di W, Li F, Zhang H, Zhou C, Fang R, Hu M. A TGF-β type II receptor that associates with developmental transition in Haemonchus contortus in vitro. PLoS Negl Trop Dis 2019; 13:e0007913. [PMID: 31790412 PMCID: PMC6938378 DOI: 10.1371/journal.pntd.0007913] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 12/31/2019] [Accepted: 11/09/2019] [Indexed: 11/19/2022] Open
Abstract
Background The TGF-β signalling pathway plays a key role in regulating dauer formation in the free-living nematode Caenorhabditis elegans, and previous work has shown that TGF-β receptors are involved in parasitic nematodes. Here, we explored the structure and function of a TGF-β type II receptor homologue in the TGF-β signalling pathway in Haemonchus contortus, a highly pathogenic, haematophagous parasitic nematode. Methodology/Principal findings Amino acid sequence and phylogenetic analyses revealed that the protein, called Hc-TGFBR2 (encoded by the gene Hc-tgfbr2), is a member of TGF-β type II receptor family and contains conserved functional domains, both in the extracellular region containing cysteine residues that form a characteristic feature (CXCX4C) of TGF-β type II receptor and in the intracellular regions containing a serine/threonine kinase domain. The Hc-tgfbr2 gene was transcribed in all key developmental stages of H. contortus, with particularly high levels in the infective third-stage larvae (L3s) and male adults. Immunohistochemical results revealed that Hc-TGFBR2 was expressed in the intestine, ovary and eggs within the uterus of female adults, and also in the testes of male adults of H. contortus. Double-stranded RNA interference (RNAi) in this nematode by soaking induced a marked decrease in transcription of Hc-tgfbr2 and in development from the exsheathed L3 to the fourth-stage larva (L4) in vitro. Conclusions/Significance These results indicate that Hc-TGFBR2 plays an important role in governing developmental processes in H. contortus via the TGF-β signalling pathway, particularly in the transition from the free-living to the parasitic stages. Haemonchus contortus is a gastrointestinal parasitic nematode that causes major economic losses in small ruminants. Here, we investigated the structure and function of a TGF-β type II receptor homologue (Hc-TGFBR2) and its role in regulating H. contortus development. The results showed that the Hc-tgfbr2 gene was transcribed in all developmental stages of H. contortus, with the highest level in L3s and male adults; the encoded protein Hc-TGFBR2 was expressed in the intestine and gonads of adult stages of this nematode. The transcriptional abundance of Hc-tgfbr2 decreased significantly following knockdown by RNA interference in xL3s of H. contortus, which also caused a marked reduction in the number of xL3s developing to L4s in vitro. These findings reveal that the TGF-β type II receptor (Hc-TGFBR2) associates with development of H. contortus, particularly in its transition from the free-living to the parasitic stage.
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Affiliation(s)
- Li He
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Robin B. Gasser
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
- Melbourne Veterinary School, Department of Veterinary Biosciences, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Tingting Li
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Wenda Di
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Fangfang Li
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Hongrun Zhang
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Caixian Zhou
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Rui Fang
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Min Hu
- State Key Laboratory of Agricultural Microbiology, Key Laboratory for the Development of Veterinary Products, Ministry of Agriculture, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
- * E-mail:
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Estrada-Reyes ZM, Tsukahara Y, Amadeu RR, Goetsch AL, Gipson TA, Sahlu T, Puchala R, Wang Z, Hart SP, Mateescu RG. Signatures of selection for resistance to Haemonchus contortus in sheep and goats. BMC Genomics 2019; 20:735. [PMID: 31615414 PMCID: PMC6792194 DOI: 10.1186/s12864-019-6150-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 09/29/2019] [Indexed: 11/20/2022] Open
Abstract
Background Gastrointestinal nematode infection (GNI) is the most important disease affecting the small ruminant industry in U.S. The environmental conditions in the southern United States are ideal for the survival of the most pathogenic gastrointestinal nematode, Haemonchus contortus. Host genetic variation for resistance to H. contortus allows selective breeding for increased resistance of animals. This selection process increases the prevalence of particular alleles in sheep and goats and creates unique genetic patterns in the genome of these species. The aim of this study was to identify loci with divergent allelic frequencies in a candidate gene panel of 100 genes using two different approaches (frequentist and Bayesian) to estimate Fst outliers in three different breeds of sheep and goats exposed to H. contortus. Results Our results for sheep populations showed SNPs under selection in C3AR1, CSF3, SOCS2, NOS2, STAT5B, TGFB2 and IL2RA genes using frequentist and Bayesian approaches. For goats, SNPs in CD1D, ITGA9, IL12A, IL13RA1, CD86 and TGFB2 genes were under selection. Common signatures of selection in both species were observed in NOS2, TGFB2 and TLR4 genes. Directional selection was present in all SNPs evaluated in the present study. Conclusions A total of 13 SNPs within 7 genes of our candidate gene panel related to H. contortus exposure were identified under selection in sheep populations. For goats, 11 SNPs within 7 genes were identified under selection. Results from this study support the hypothesis that resistance to H. contortus is likely to be controlled by many loci. Shared signatures of selection related to mechanisms of immune protection against H. contortus infection in sheep and goats could be useful targets in breeding programs aimed to produce resistant animals with low FEC.
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Affiliation(s)
| | - Yoko Tsukahara
- American Institute for Goat Research, Langston University, Langston, OK, USA
| | - Rodrigo R Amadeu
- Horticultural Sciences Department, University of Florida, Gainesville, FL, USA
| | - Arthur L Goetsch
- American Institute for Goat Research, Langston University, Langston, OK, USA
| | - Terry A Gipson
- American Institute for Goat Research, Langston University, Langston, OK, USA
| | - Tilahun Sahlu
- American Institute for Goat Research, Langston University, Langston, OK, USA
| | - Richard Puchala
- American Institute for Goat Research, Langston University, Langston, OK, USA
| | - Zaisen Wang
- American Institute for Goat Research, Langston University, Langston, OK, USA
| | - Steve P Hart
- American Institute for Goat Research, Langston University, Langston, OK, USA
| | - Raluca G Mateescu
- Department of Animal Sciences, University of Florida, Gainesville, FL, USA
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Ma G, Wang T, Korhonen PK, Stroehlein AJ, Young ND, Gasser RB. Dauer signalling pathway model for Haemonchus contortus. Parasit Vectors 2019; 12:187. [PMID: 31036054 PMCID: PMC6489264 DOI: 10.1186/s13071-019-3419-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 03/28/2019] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Signalling pathways have been extensively investigated in the free-living nematode Caenorhabditis elegans, but very little is known about these pathways in parasitic nematodes. Here, we constructed a model for the dauer-associated signalling pathways in an economically highly significant parasitic worm, Haemonchus contortus. METHODS Guided by data and information available for C. elegans, we used extensive genomic and transcriptomic datasets to infer gene homologues in the dauer-associated pathways, explore developmental transcriptomic, proteomic and phosphoproteomic profiles in H. contortus and study selected molecular structures. RESULTS The canonical cyclic guanosine monophosphate (cGMP), transforming growth factor-β (TGF-β), insulin-like growth factor 1 (IGF-1) and steroid hormone signalling pathways of H. contortus were inferred to represent a total of 61 gene homologues. Compared with C. elegans, H. contortus has a reduced set of genes encoding insulin-like peptides, implying evolutionary and biological divergences between the parasitic and free-living nematodes. Similar transcription profiles were found for all gene homologues between the infective stage of H. contortus and dauer stage of C. elegans. High transcriptional levels for genes encoding G protein-coupled receptors (GPCRs), TGF-β, insulin-like ligands (e.g. ins-1, ins-17 and ins-18) and transcriptional factors (e.g. daf-16) in the infective L3 stage of H. contortus were suggestive of critical functional roles in this stage. Conspicuous protein expression patterns and extensive phosphorylation of some components of these pathways suggested marked post-translational modifications also in the L3 stage. The high structural similarity in the DAF-12 ligand binding domain among nematodes indicated functional conservation in steroid (i.e. dafachronic acid) signalling linked to worm development. CONCLUSIONS Taken together, this pathway model provides a basis to explore hypotheses regarding biological processes and regulatory mechanisms (via particular microRNAs, phosphorylation events and/or lipids) associated with the development of H. contortus and related nematodes as well as parasite-host cross talk, which could aid the discovery of new therapeutic targets.
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Affiliation(s)
- Guangxu Ma
- Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC 3010 Australia
| | - Tao Wang
- Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC 3010 Australia
| | - Pasi K. Korhonen
- Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC 3010 Australia
| | - Andreas J. Stroehlein
- Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC 3010 Australia
| | - Neil D. Young
- Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC 3010 Australia
| | - Robin B. Gasser
- Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne, Parkville, VIC 3010 Australia
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Zakeri A, Hansen EP, Andersen SD, Williams AR, Nejsum P. Immunomodulation by Helminths: Intracellular Pathways and Extracellular Vesicles. Front Immunol 2018; 9:2349. [PMID: 30369927 PMCID: PMC6194161 DOI: 10.3389/fimmu.2018.02349] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 09/21/2018] [Indexed: 12/13/2022] Open
Abstract
Helminth parasites are masters at manipulating host immune responses, using an array of sophisticated mechanisms. One of the major mechanisms enabling helminths to establish chronic infections is the targeting of pattern recognition receptors (PRRs) including toll-like receptors, C-type lectin receptors, and the inflammasome. Given the critical role of these receptors and their intracellular pathways in regulating innate inflammatory responses, and also directing adaptive immunity toward Th1 and Th2 responses, recognition of the pathways triggered and/or modulated by helminths and their products will provide detailed insights about how helminths are able to establish an immunoregulatory environment. However, helminths also target PRRs-independent mechanisms (and most likely other yet unknown mechanisms and pathways) underpinning the battery of different molecules helminths produce. Herein, the current knowledge on intracellular pathways in antigen presenting cells activated by helminth-derived biomolecules is reviewed. Furthermore, we discuss the importance of helminth-derived vesicles as a less-appreciated components released during infection, their role in activating these host intracellular pathways, and their implication in the development of new therapeutic approaches for inflammatory diseases and the possibility of designing a new generation of vaccines.
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Affiliation(s)
- Amin Zakeri
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Eline P. Hansen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Sidsel D. Andersen
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
| | - Andrew R. Williams
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Peter Nejsum
- Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
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Musah-Eroje M, Flynn RJ. Fasciola hepatica, TGF-β and host mimicry: the enemy within. Curr Opin Microbiol 2018; 46:80-85. [PMID: 30317150 DOI: 10.1016/j.mib.2018.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 08/29/2018] [Accepted: 09/24/2018] [Indexed: 11/16/2022]
Abstract
Helminths parasites undergo developmental changes and migration within their definitive host, in addition to establishing chronic infection. Essential to this is the evasion of host immune responses; the canonical Th2 response is effective at removing parasites resident in the intestine. Conversely, helminths also promote the development of antigen-specific anergy and regulation. This often limits pathology but allows parasite survival, parasite effectors mediating this are the subject of intense study. They may be useful as future vaccine targets or xenogenic therapeutics. Fasciola hepatica possesses a family of TGF-like molecules of which one member, FhTLM, is capable of promoting intrinsic and extrinsic effects. Here we review the extrinsic effects of FhTLM on the host macrophage and its consequences for protective immunity. This review also discusses the specificities of FhTLM in light a very recent description of a nematode TGF-β mimic and the effects of endogenous TGF-β.
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Affiliation(s)
- Mayowa Musah-Eroje
- School of Veterinary Medicine and Science, University of Nottingham, LE12 5RD, United Kingdom
| | - Robin J Flynn
- Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, L3 5RF, United Kingdom.
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Smyth DJ, Harcus Y, White MPJ, Gregory WF, Nahler J, Stephens I, Toke-Bjolgerud E, Hewitson JP, Ivens A, McSorley HJ, Maizels RM. TGF-β mimic proteins form an extended gene family in the murine parasite Heligmosomoides polygyrus. Int J Parasitol 2018; 48:379-385. [PMID: 29510118 PMCID: PMC5904571 DOI: 10.1016/j.ijpara.2017.12.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 12/05/2017] [Accepted: 12/19/2017] [Indexed: 12/24/2022]
Abstract
We recently reported the discovery of a new parasite-derived protein that functionally mimics the immunosuppressive cytokine transforming growth factor (TGF)-β. The Heligmosomoides polygyrus TGF-β Mimic (Hp-TGM) shares no homology to any TGF-β family member, however it binds the mammalian TGF-β receptor and induces expression of Foxp3, the canonical transcription factor of both mouse and human regulatory T cells. Hp-TGM consists of five atypical Complement Control Protein (CCP, Pfam 00084) domains, each lacking certain conserved residues and 12-15 amino acids longer than the 60-70 amino acids consensus domain, but with a recognizable 3-cysteine, tryptophan, cysteine motif. We now report on the identification of a family of nine related Hp-TGM homologues represented in the secreted proteome and transcriptome of H. polygyrus. Recombinant proteins from five of the nine new TGM members were tested for TGF-β activity, but only two were functionally active in an MFB-F11 reporter assay, and by the induction of T cell Foxp3 expression. Sequence comparisons reveal that proteins with functional activity are similar or identical to Hp-TGM across the first three CCP domains, but more variable in domains 4 and 5. Inactive proteins diverged in all domains, or lacked some domains entirely. Testing truncated versions of Hp-TGM confirmed that domains 1-3 are essential for full activity in vitro, while domains 4 and 5 are not required. Further studies will elucidate whether these latter domains fulfill other functions in promoting host immune regulation during infection and if the more divergent family members play other roles in immunomodulation.
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Affiliation(s)
- Danielle J Smyth
- Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
| | - Yvonne Harcus
- Institute of Infection and Immunology Research and Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, UK
| | - Madeleine P J White
- Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
| | - William F Gregory
- Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
| | - Janina Nahler
- MRC Weatherall Institute of Molecular Medicine, University of Oxford, UK
| | - Ian Stephens
- Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
| | - Edward Toke-Bjolgerud
- Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK
| | - James P Hewitson
- Centre for Infection and Immunology, Department of Biology, University of York, UK
| | - Alasdair Ivens
- Institute of Infection and Immunology Research and Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, UK
| | - Henry J McSorley
- Institute of Infection and Immunology Research and Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, UK; MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, UK
| | - Rick M Maizels
- Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, UK; Institute of Infection and Immunology Research and Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, UK.
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23
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A structurally distinct TGF-β mimic from an intestinal helminth parasite potently induces regulatory T cells. Nat Commun 2017; 8:1741. [PMID: 29170498 PMCID: PMC5701006 DOI: 10.1038/s41467-017-01886-6] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 10/23/2017] [Indexed: 01/06/2023] Open
Abstract
Helminth parasites defy immune exclusion through sophisticated evasion mechanisms, including activation of host immunosuppressive regulatory T (Treg) cells. The mouse parasite Heligmosomoides polygyrus can expand the host Treg population by secreting products that activate TGF-β signalling, but the identity of the active molecule is unknown. Here we identify an H. polygyrus TGF-β mimic (Hp-TGM) that replicates the biological and functional properties of TGF-β, including binding to mammalian TGF-β receptors and inducing mouse and human Foxp3+ Treg cells. Hp-TGM has no homology with mammalian TGF-β or other members of the TGF-β family, but is a member of the complement control protein superfamily. Thus, our data indicate that through convergent evolution, the parasite has acquired a protein with cytokine-like function that is able to exploit an endogenous pathway of immunoregulation in the host. Heligmosomoides polygyrus can activate mammalian TGF-β signalling pathways, but how it does so is not known. Here the authors identify and isolate a H. polygyrus TFG-β mimic that can bind both mammalian TGF-β receptor subunits, activate Smad signalling and generate inducible regulatory T cells.
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24
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Grubor NM, Jovanova-Nesic KD, Shoenfeld Y. Liver cystic echinococcosis and human host immune and autoimmune follow-up: A review. World J Hepatol 2017; 9:1176-1189. [PMID: 29109850 PMCID: PMC5666304 DOI: 10.4254/wjh.v9.i30.1176] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Revised: 08/28/2017] [Accepted: 09/14/2017] [Indexed: 02/06/2023] Open
Abstract
Cystic echinococcosis (CE) is an infectious disease caused by the larvae of parasite Echinococcus granulosus (E. granulosus). To successfully establish an infection, parasite release some substances and molecules that can modulate host immune functions, stimulating a strong anti-inflammatory reaction to carry favor to host and to reserve self-survival in the host. The literature was reviewed using MEDLINE, and an open access search for immunology of hydatidosis was performed. Accumulating data from animal experiments and human studies provided us with exciting insights into the mechanisms involved that affect all parts of immunity. In this review we used the existing scientific data and discuss how these findings assisted with a better understanding of the immunology of E. granulosus infection in man. The aim of this study is to point the several facts that challenge immune and autoimmune responses to protect E. granulosus from elimination and to minimize host severe pathology. Understanding the immune mechanisms of E. granulosus infection in an intermediate human host will provide, we believe, a more useful treatment with immunomodulating molecules and possibly better protection from parasitic infections. Besides that, the diagnosis of CE has improved due to the application of a new molecular tool for parasite identification by using of new recombinant antigens and immunogenic peptides. More studies for the better understanding of the mechanisms of parasite immune evasion is necessary. It will enable a novel approach in protection, detection and improving of the host inflammatory responses. In contrast, according to the "hygiene hypothesis", clinical applications that decrease the incidence of infection in developed countries and recently in developing countries are at the origin of the increasing incidence of both allergic and autoimmune diseases. Thus, an understanding of the immune mechanisms of E. granulosus infection is extremely important.
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Affiliation(s)
- Nikica M Grubor
- Department of Hepatobiliary and Pancreatic Surgery, First Surgical University Hospital, Clinical Center of Serbia, School of Medicine University of Belgrade, 11000 Belgrade, Serbia
| | - Katica D Jovanova-Nesic
- Immunology Research Center, Institute of Virology, Vaccine and Sera-Torlak, 11221 Belgrade, Serbia
- European Center for Peace and Development, University for Peace in the United Nation established in Belgrade, 11000 Belgrade, Serbia.
| | - Yehuda Shoenfeld
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Aviv University, 5265601 Tel-Hashomer, Tel Aviv, Israel
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25
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Lippens C, Guivier E, Ollivier A, Faivre B, Sorci G. Life history adjustments to intestinal inflammation in a gut nematode. J Exp Biol 2017; 220:3724-3732. [DOI: 10.1242/jeb.161059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 08/10/2017] [Indexed: 11/20/2022]
Abstract
ABSTRACT
Many parasitic nematodes establish chronic infections. This implies a finely tuned interaction with the host immune response in order to avoid infection clearance. Although a number of immune interference mechanisms have been described in nematodes, how parasites adapt to the immune environment provided by their hosts remains largely unexplored. Here, we used the gastrointestinal nematode Heligmosomoides polygyrus to investigate the plasticity of life history traits and immunomodulatory mechanisms in response to intestinal inflammation. We adopted an experimental model of induced colitis and exposed worms to intestinal inflammation at two different developmental stages (larvae and adults). We found that H. polygyrus responded to intestinal inflammation by up-regulating the expression of a candidate gene involved in the interference with the host immune response. Worms infecting mice with colitis also had better infectivity (earlier adult emergence in the intestinal lumen and higher survival) compared with worms infecting control hosts, suggesting that H. polygyrus adjusted its life history schedule in response to intestinal inflammation.
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Affiliation(s)
- Cédric Lippens
- Biogéosciences, CNRS UMR 6282, Université de Bourgogne Franche-Comté, 6 boulevard Gabriel, 21000 Dijon, France
| | - Emmanuel Guivier
- Biogéosciences, CNRS UMR 6282, Université de Bourgogne Franche-Comté, 6 boulevard Gabriel, 21000 Dijon, France
- Institut Méditerranéen de la Biodiversité et d'Ecologie marine et continentale (IMBE, UMR Université Aix Marseille/CNRS 7263/IRD 237/Avignon Université), France
| | - Anthony Ollivier
- Biogéosciences, CNRS UMR 6282, Université de Bourgogne Franche-Comté, 6 boulevard Gabriel, 21000 Dijon, France
| | - Bruno Faivre
- Biogéosciences, CNRS UMR 6282, Université de Bourgogne Franche-Comté, 6 boulevard Gabriel, 21000 Dijon, France
| | - Gabriele Sorci
- Biogéosciences, CNRS UMR 6282, Université de Bourgogne Franche-Comté, 6 boulevard Gabriel, 21000 Dijon, France
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26
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Guivier E, Lippens C, Faivre B, Sorci G. Plastic and micro-evolutionary responses of a nematode to the host immune environment. Exp Parasitol 2017; 181:14-22. [PMID: 28733132 DOI: 10.1016/j.exppara.2017.07.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 05/31/2017] [Accepted: 07/17/2017] [Indexed: 12/18/2022]
Abstract
Parasitic organisms have to cope with the defences deployed by their hosts and this can be achieved adopting immune evasion strategies or optimal life history traits according to the prevailing pattern of immune-mediated mortality. Parasites often encounter variable immune environments both within and between hosts, promoting the evolution of plastic strategies instead of fixed responses. Here, we explored the plasticity and micro-evolutionary responses of immunomodulatory mechanisms and life history traits to the immune environment provided by the host, using the parasitic nematode Heligmosomoides polygyrus. To test if the parasite responds plastically to the immune environment, we stimulated the systemic inflammatory response of mice and we assessed i) the expression of two genes with candidate immunomodulatory functions (Hp-Tgh2 and Hp-CPI); ii) changes in the number of eggs shed in the faeces. To test if the immune environment induces a micro-evolutionary response in the parasite, we maintained the nematode in mice whose inflammatory response was up- or down-regulated during four generations. We found that H. polygyrus plastically responded to a sudden rise of pro-inflammatory cytokines, up-regulating the expression of two candidate genes involved in the process of immune modulation, and enhancing egg output. At the micro-evolutionary level, parasites maintained in hosts experiencing different levels of inflammation did not have differential expression of Hp-Tgh2 and Hp-CPI genes when infecting unmanipulated, control, mice. However, parasites maintained in mice with an up-regulated inflammation shed more eggs compared to the control line. Overall, our study shows that H. polygyrus can plastically adjust the expression of immunomodulatory genes and life history traits, and responds to selection exerted by the host immune system.
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Affiliation(s)
- Emmanuel Guivier
- Biogéosciences, CNRS UMR 6282, Université de Bourgogne Franche-Comté, 6 Bd Gabriel, 21000 Dijon, France; Physiopathologie des dyslipidémies, INSERM UMR 866, Université de Bourgogne Franche-Comté, 21000 Dijon, France.
| | - Cédric Lippens
- Biogéosciences, CNRS UMR 6282, Université de Bourgogne Franche-Comté, 6 Bd Gabriel, 21000 Dijon, France
| | - Bruno Faivre
- Biogéosciences, CNRS UMR 6282, Université de Bourgogne Franche-Comté, 6 Bd Gabriel, 21000 Dijon, France
| | - Gabriele Sorci
- Biogéosciences, CNRS UMR 6282, Université de Bourgogne Franche-Comté, 6 Bd Gabriel, 21000 Dijon, France
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27
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Smallwood TB, Giacomin PR, Loukas A, Mulvenna JP, Clark RJ, Miles JJ. Helminth Immunomodulation in Autoimmune Disease. Front Immunol 2017; 8:453. [PMID: 28484453 PMCID: PMC5401880 DOI: 10.3389/fimmu.2017.00453] [Citation(s) in RCA: 159] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 04/03/2017] [Indexed: 12/26/2022] Open
Abstract
Helminths have evolved to become experts at subverting immune surveillance. Through potent and persistent immune tempering, helminths can remain undetected in human tissues for decades. Redirecting the immunomodulating "talents" of helminths to treat inflammatory human diseases is receiving intensive interest. Here, we review therapies using live parasitic worms, worm secretions, and worm-derived synthetic molecules to treat autoimmune disease. We review helminth therapy in both mouse models and clinical trials and discuss what is known on mechanisms of action. We also highlight current progress in characterizing promising new immunomodulatory molecules found in excretory/secretory products of helminths and their potential use as immunotherapies for acute and chronic inflammatory diseases.
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Affiliation(s)
- Taylor B Smallwood
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
| | - Paul R Giacomin
- Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Alex Loukas
- Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Jason P Mulvenna
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.,Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia.,QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Richard J Clark
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
| | - John J Miles
- Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia.,QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.,School of Medicine, The University of Queensland, Brisbane, QLD, Australia
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28
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Lok JB. Signaling in Parasitic Nematodes: Physicochemical Communication Between Host and Parasite and Endogenous Molecular Transduction Pathways Governing Worm Development and Survival. CURRENT CLINICAL MICROBIOLOGY REPORTS 2016; 3:186-197. [PMID: 28781934 PMCID: PMC5543980 DOI: 10.1007/s40588-016-0046-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Signaling or communication between host and parasite may occur over relatively long ranges to enable host finding and acquisition by infective parasitic nematode larvae. Innate behaviors in infective larvae transmitted from the soil that enhance the likelihood of host contact, such as negative geotaxis and hypermotility, are likely mediated by mechanoreception and neuromuscular signaling. Host cues such as vibration of the substratum, elevated temperature, exhaled CO2, and other volatile odorants are perceived by mechanosensory and chemosensory neurons of the amphidial complex. Beyond this, the molecular systems that transduce these external cues within the worm are unknown at this time. Overall, the signal transduction mechanisms that regulate switching between dauer and continuous reproductive development in Caenorhabditis elegans, and doubtless other free-living nematodes, have provided a useful framework for testing hypotheses about how the morphogenesis and development of infective parasitic nematode larvae and the lifespan of adult parasites are regulated. In C. elegans, four major signal transduction pathways, G protein-coupled receptor signaling, insulin/insulin-like growth factor signaling, TGFβ-like signaling and steroid-nuclear hormone receptor signaling govern the switch between dauer and continuous development and regulate adult lifespan. Parasitic nematodes appear to have conserved the functions of G-protein-coupled signaling, insulin-like signaling and steroid-nuclear hormone receptor signaling to regulate larval development before and during the infective process. By contrast, TGFβ-like signaling appears to have been adapted for some other function, perhaps modulation of the host immune response. Of the three signal transduction pathways that appear to regulate development in parasitic nematodes, steroid-nuclear hormone signaling is the most straightforward to manipulate with administered small molecules and may form the basis of new chemotherapeutic strategies. Signaling between parasites and their hosts' immune systems also occurs and serves to modulate these responses to allow chronic infection and down regulate acute inflammatory responses. Knowledge of the precise nature of this signaling may form the basis of immunological interventions to protect against parasitism or related lesions and to alleviate inflammatory diseases of various etiologies.
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Affiliation(s)
- James B Lok
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104 USA
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29
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Rehman ZU, Knight JS, Koolaard J, Simpson HV, Pernthaner A. Immunomodulatory effects of adult Haemonchus contortus excretory/secretory products on human monocyte-derived dendritic cells. Parasite Immunol 2016; 37:657-69. [PMID: 26457886 DOI: 10.1111/pim.12288] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 10/05/2015] [Indexed: 12/13/2022]
Abstract
The levels of expression of surface molecules and release of cytokines and chemokines of human monocyte-derived dendritic cells were determined after their exposure to adult H. contortus excretory/secretory (ES) products or a combination of ES products and bacterial lipopolysaccharide (LPS). Worm products provoked a weak response and only partial maturation of the dendritic cells, consistent with the hyporesponsiveness and more tolerogenic immune environment present in parasitized animals and humans. Co-stimulation with LPS demonstrated that H. contortus secretions, like those of other helminths, contain immunomodulators capable of reducing some aspects of the strong T(H)1/T(H)2 response evoked by bacterial LPS. There were significant reductions in the release of some cytokine/chemokines by LPS-stimulated mdDCs and a trend (although not significant at P < 0.05) for reduced expression levels of CD40, CD80 and HLA-DR. A prominent feature was the variability in responses of dendritic cells from the four donors, even on different days in repeat experiments, suggesting that generalized conclusions may be difficult to make, except in genetically related animals. Such observations may therefore be applicable only to restricted populations. In addition, previous exposure to parasites in a target population for immunomodulatory therapy may be an important factor in assessing the likelihood of adverse reactions or failures in the treatment to worm therapy.
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Affiliation(s)
- Z U Rehman
- Institute of Veterinary Animal and Biological Sciences, Massey University, Palmerston North, New Zealand
| | - J S Knight
- The Hopkirk Research Institute, AgResearch Ltd, Palmerston North, New Zealand
| | - J Koolaard
- Grasslands Research Centre, AgResearch Ltd, Palmerston North, New Zealand
| | - H V Simpson
- Institute of Veterinary Animal and Biological Sciences, Massey University, Palmerston North, New Zealand
| | - A Pernthaner
- The Hopkirk Research Institute, AgResearch Ltd, Palmerston North, New Zealand
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30
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Armstrong SD, Xia D, Bah GS, Krishna R, Ngangyung HF, LaCourse EJ, McSorley HJ, Kengne-Ouafo JA, Chounna-Ndongmo PW, Wanji S, Enyong PA, Taylor DW, Blaxter ML, Wastling JM, Tanya VN, Makepeace BL. Stage-specific Proteomes from Onchocerca ochengi, Sister Species of the Human River Blindness Parasite, Uncover Adaptations to a Nodular Lifestyle. Mol Cell Proteomics 2016; 15:2554-75. [PMID: 27226403 PMCID: PMC4974336 DOI: 10.1074/mcp.m115.055640] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Revised: 04/30/2016] [Indexed: 12/13/2022] Open
Abstract
Despite 40 years of control efforts, onchocerciasis (river blindness) remains one of the most important neglected tropical diseases, with 17 million people affected. The etiological agent, Onchocerca volvulus, is a filarial nematode with a complex lifecycle involving several distinct stages in the definitive host and blackfly vector. The challenges of obtaining sufficient material have prevented high-throughput studies and the development of novel strategies for disease control and diagnosis. Here, we utilize the closest relative of O. volvulus, the bovine parasite Onchocerca ochengi, to compare stage-specific proteomes and host-parasite interactions within the secretome. We identified a total of 4260 unique O. ochengi proteins from adult males and females, infective larvae, intrauterine microfilariae, and fluid from intradermal nodules. In addition, 135 proteins were detected from the obligate Wolbachia symbiont. Observed protein families that were enriched in all whole body extracts relative to the complete search database included immunoglobulin-domain proteins, whereas redox and detoxification enzymes and proteins involved in intracellular transport displayed stage-specific overrepresentation. Unexpectedly, the larval stages exhibited enrichment for several mitochondrial-related protein families, including members of peptidase family M16 and proteins which mediate mitochondrial fission and fusion. Quantification of proteins across the lifecycle using the Hi-3 approach supported these qualitative analyses. In nodule fluid, we identified 94 O. ochengi secreted proteins, including homologs of transforming growth factor-β and a second member of a novel 6-ShK toxin domain family, which was originally described from a model filarial nematode (Litomosoides sigmodontis). Strikingly, the 498 bovine proteins identified in nodule fluid were strongly dominated by antimicrobial proteins, especially cathelicidins. This first high-throughput analysis of an Onchocerca spp. proteome across the lifecycle highlights its profound complexity and emphasizes the extremely close relationship between O. ochengi and O. volvulus The insights presented here provide new candidates for vaccine development, drug targeting and diagnostic biomarkers.
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Affiliation(s)
- Stuart D Armstrong
- From the ‡Institute of Infection & Global Health, University of Liverpool, Liverpool L3 5RF, UK
| | - Dong Xia
- From the ‡Institute of Infection & Global Health, University of Liverpool, Liverpool L3 5RF, UK
| | - Germanus S Bah
- §Institut de Recherche Agricole pour le Développement, Regional Centre of Wakwa, BP65 Ngaoundéré, Cameroon
| | - Ritesh Krishna
- ¶Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK
| | - Henrietta F Ngangyung
- §Institut de Recherche Agricole pour le Développement, Regional Centre of Wakwa, BP65 Ngaoundéré, Cameroon
| | - E James LaCourse
- ‖Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK
| | - Henry J McSorley
- **The Queens Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4JT
| | - Jonas A Kengne-Ouafo
- ‡‡Research Foundation for Tropical Diseases and Environment, PO Box 474 Buea, Cameroon
| | | | - Samuel Wanji
- ‡‡Research Foundation for Tropical Diseases and Environment, PO Box 474 Buea, Cameroon
| | - Peter A Enyong
- ‡‡Research Foundation for Tropical Diseases and Environment, PO Box 474 Buea, Cameroon; §§Tropical Medicine Research Station, Kumba, Cameroon
| | - David W Taylor
- From the ‡Institute of Infection & Global Health, University of Liverpool, Liverpool L3 5RF, UK; ¶¶Division of Pathway Medicine, University of Edinburgh, Edinburgh EH9 3JT, UK
| | - Mark L Blaxter
- ‖‖Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, UK
| | - Jonathan M Wastling
- From the ‡Institute of Infection & Global Health, University of Liverpool, Liverpool L3 5RF, UK; ‡‡‡The National Institute for Health Research, Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool L3 5RF, UK
| | - Vincent N Tanya
- §Institut de Recherche Agricole pour le Développement, Regional Centre of Wakwa, BP65 Ngaoundéré, Cameroon
| | - Benjamin L Makepeace
- From the ‡Institute of Infection & Global Health, University of Liverpool, Liverpool L3 5RF, UK;
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31
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Gilabert A, Curran DM, Harvey SC, Wasmuth JD. Expanding the view on the evolution of the nematode dauer signalling pathways: refinement through gene gain and pathway co-option. BMC Genomics 2016; 17:476. [PMID: 27350342 PMCID: PMC4924289 DOI: 10.1186/s12864-016-2770-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2015] [Accepted: 05/25/2016] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Signalling pathways underlie development, behaviour and pathology. To understand patterns in the evolution of signalling pathways, we undertook a comprehensive investigation of the pathways that control the switch between growth and developmentally quiescent dauer in 24 species of nematodes spanning the phylum. RESULTS Our analysis of 47 genes across these species indicates that the pathways and their interactions are not conserved throughout the Nematoda. For example, the TGF-β pathway was co-opted into dauer control relatively late in a lineage that led to the model species Caenorhabditis elegans. We show molecular adaptations described in C. elegans that are restricted to its genus or even just to the species. Similarly, our analyses both identify species where particular genes have been lost and situations where apparently incorrect orthologues have been identified. CONCLUSIONS Our analysis also highlights the difficulties of working with genome sequences from non-model species as reliance on the published gene models would have significantly restricted our understanding of how signalling pathways evolve. Our approach therefore offers a robust standard operating procedure for genomic comparisons.
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Affiliation(s)
- Aude Gilabert
- Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada
- Current address: MIVEGEC (UMR CNRS/IRD/UM 5290), Montpellier, France
| | - David M Curran
- Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada
| | - Simon C Harvey
- Biomolecular Research Group, School of Human and Life Sciences, Canterbury Christ Church University, Canterbury, UK
| | - James D Wasmuth
- Department of Ecosystem and Public Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada.
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32
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Johnston CJC, Smyth DJ, Dresser DW, Maizels RM. TGF-β in tolerance, development and regulation of immunity. Cell Immunol 2015; 299:14-22. [PMID: 26617281 PMCID: PMC4711336 DOI: 10.1016/j.cellimm.2015.10.006] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 10/20/2015] [Accepted: 10/21/2015] [Indexed: 12/20/2022]
Abstract
The broader superfamily of TGF-β-like proteins is reviewed, and signaling pathways summarised. The role of TGF-β in the immune tolerance and control of infectious disease is discussed. The superfamily member AMH is involved in embryonic sexual differentiation. Helminth parasites appear to exploit the TGF-β pathway to suppress host immunity. TGF-β homologues and mimics from parasites offer a new route for therapeutic tolerance induction. The TGF-β superfamily is an ancient metazoan protein class which cuts across cell and tissue differentiation, developmental biology and immunology. Its many members are regulated at multiple levels from intricate control of gene transcription, post-translational processing and activation, and signaling through overlapping receptor structures and downstream intracellular messengers. We have been interested in TGF-β homologues firstly as key players in the induction of immunological tolerance, the topic so closely associated with Ray Owen. Secondly, our interests in how parasites may manipulate the immune system of their host has also brought us to study the TGF-β pathway in infections with longlived, essentially tolerogenic, helminth parasites. Finally, within the spectrum of mammalian TGF-β proteins is an exquisitely tightly-regulated gene, anti-Müllerian hormone (AMH), whose role in sex determination underpins the phenotype of freemartin calves that formed the focus of Ray’s seminal work on immunological tolerance.
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Affiliation(s)
- Chris J C Johnston
- Institute of Immunology and Infection Research, University of Edinburgh, UK
| | - Danielle J Smyth
- Institute of Immunology and Infection Research, University of Edinburgh, UK
| | - David W Dresser
- Institute of Immunology and Infection Research, University of Edinburgh, UK
| | - Rick M Maizels
- Institute of Immunology and Infection Research, University of Edinburgh, UK.
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Japa O, Hodgkinson JE, Emes RD, Flynn RJ. TGF-β superfamily members from the helminth Fasciola hepatica show intrinsic effects on viability and development. Vet Res 2015; 46:29. [PMID: 25879787 PMCID: PMC4354977 DOI: 10.1186/s13567-015-0167-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 02/25/2015] [Indexed: 12/31/2022] Open
Abstract
The helminth Fasciola hepatica causes fasciolosis throughout the world, a major disease of livestock and an emerging zoonotic disease in humans. Sustainable control mechanisms such as vaccination are urgently required. To discover potential vaccine targets we undertook a genome screen to identify members of the transforming growth factor (TGF) family of proteins. Herein we describe the discovery of three ligands belonging to this superfamily and the cloning and characterisation of an activin/TGF like molecule we term FhTLM. FhTLM has a limited expression pattern both temporally across the parasite stages but also spatially within the worm. Furthermore, a recombinant form of this protein is able to enhance the rate (or magnitude) of multiple developmental processes of the parasite indicating a conserved role for this protein superfamily in the developmental biology of a major trematode parasite. Our study demonstrates for the first time the existence of this protein superfamily within F. hepatica and assigns a function to one of the three identified ligands. Moreover further exploration of this superfamily may yield future targets for diagnostic or vaccination purposes due to its stage restricted expression and functional role.
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Affiliation(s)
- Ornampai Japa
- School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham, LE12 5RD, UK.
| | - Jane E Hodgkinson
- Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool, L3 5RF, UK.
| | - Richard D Emes
- School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham, LE12 5RD, UK.
- Advanced Data Analysis Centre, University of Nottingham, Sutton Bonington, Nottingham, LE12 5RD, UK.
| | - Robin J Flynn
- School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, Nottingham, LE12 5RD, UK.
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Grainger JR, Askenase MH, Guimont-Desrochers F, da Fonseca DM, Belkaid Y. Contextual functions of antigen-presenting cells in the gastrointestinal tract. Immunol Rev 2014; 259:75-87. [PMID: 24712460 DOI: 10.1111/imr.12167] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The immune system of the gastrointestinal tract must be tightly regulated to limit pathologic responses toward innocuous antigens while simultaneously allowing for rapid development of effector responses against invading pathogens. Highly specialized antigen-presenting cell (APC) subsets present in the gut play a dominant role in balancing these seemingly disparate functions. In this review, we discuss new findings associated with the function of gut APCs and particularly the contextual role of these cells in both establishing tolerance to orally acquired antigens in the steady state and regulating acute inflammation during infection.
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Affiliation(s)
- John R Grainger
- Program in Barrier Immunity and Repair, Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
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35
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McNeilly TN, Nisbet AJ. Immune modulation by helminth parasites of ruminants: implications for vaccine development and host immune competence. ACTA ACUST UNITED AC 2014; 21:51. [PMID: 25292481 PMCID: PMC4189095 DOI: 10.1051/parasite/2014051] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2014] [Accepted: 09/21/2014] [Indexed: 12/20/2022]
Abstract
Parasitic helminths reside in immunologically-exposed extracellular locations within their hosts, yet they are capable of surviving for extended periods. To enable this survival, these parasites have developed complex and multifaceted mechanisms to subvert or suppress host immunity. This review summarises current knowledge of immune modulation by helminth parasites of ruminants and the parasite-derived molecules involved in driving this modulation. Such immunomodulatory molecules have considerable promise as vaccine targets, as neutralisation of their function is predicted to enhance anti-parasite immunity and, as such, current knowledge in this area is presented herein. Furthermore, we summarise current evidence that, as well as affecting parasite-specific immunity, immune modulation by these parasites may also affect the ability of ruminant hosts to control concurrent diseases or mount effective responses to vaccination.
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Affiliation(s)
- Tom N McNeilly
- Disease Control, Moredun Research Institute, Pentlands Science Park, EH26 OPZ, UK
| | - Alasdair J Nisbet
- Vaccines and Diagnostics, Moredun Research Institute, Pentlands Science Park, EH26 OPZ, UK
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36
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Stoltzfus JD, Bart SM, Lok JB. cGMP and NHR signaling co-regulate expression of insulin-like peptides and developmental activation of infective larvae in Strongyloides stercoralis. PLoS Pathog 2014; 10:e1004235. [PMID: 25010340 PMCID: PMC4092141 DOI: 10.1371/journal.ppat.1004235] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 05/21/2014] [Indexed: 01/18/2023] Open
Abstract
The infectious form of the parasitic nematode Strongyloides stercoralis is a developmentally arrested third-stage larva (L3i), which is morphologically similar to the developmentally arrested dauer larva in the free-living nematode Caenorhabditis elegans. We hypothesize that the molecular pathways regulating C. elegans dauer development also control L3i arrest and activation in S. stercoralis. This study aimed to determine the factors that regulate L3i activation, with a focus on G protein-coupled receptor-mediated regulation of cyclic guanosine monophosphate (cGMP) pathway signaling, including its modulation of the insulin/IGF-1-like signaling (IIS) pathway. We found that application of the membrane-permeable cGMP analog 8-bromo-cGMP potently activated development of S. stercoralis L3i, as measured by resumption of feeding, with 85.1 ± 2.2% of L3i feeding in 200 µM 8-bromo-cGMP in comparison to 0.6 ± 0.3% in the buffer diluent. Utilizing RNAseq, we examined L3i stimulated with DMEM, 8-bromo-cGMP, or the DAF-12 nuclear hormone receptor (NHR) ligand Δ7-dafachronic acid (DA)--a signaling pathway downstream of IIS in C. elegans. L3i stimulated with 8-bromo-cGMP up-regulated transcripts of the putative agonistic insulin-like peptide (ILP) -encoding genes Ss-ilp-1 (20-fold) and Ss-ilp-6 (11-fold) in comparison to controls without stimulation. Surprisingly, we found that Δ7-DA similarly modulated transcript levels of ILP-encoding genes. Using the phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitor LY294002, we demonstrated that 400 nM Δ7-DA-mediated activation (93.3 ± 1.1% L3i feeding) can be blocked using this IIS inhibitor at 100 µM (7.6 ± 1.6% L3i feeding). To determine the tissues where promoters of ILP-encoding genes are active, we expressed promoter::egfp reporter constructs in transgenic S. stercoralis post-free-living larvae. Ss-ilp-1 and Ss-ilp-6 promoters are active in the hypodermis and neurons and the Ss-ilp-7 promoter is active in the intestine and a pair of head neurons. Together, these data provide evidence that cGMP and DAF-12 NHR signaling converge on IIS to regulate S. stercoralis L3i activation.
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Affiliation(s)
- Jonathan D. Stoltzfus
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America
- Department of Biology, Hollins University, Roanoke, Virginia, United States of America
| | - Stephen M. Bart
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America
| | - James B. Lok
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America
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Hewitson JP, Rückerl D, Harcus Y, Murray J, Webb LM, Babayan SA, Allen JE, Kurniawan A, Maizels RM. The secreted triose phosphate isomerase of Brugia malayi is required to sustain microfilaria production in vivo. PLoS Pathog 2014; 10:e1003930. [PMID: 24586152 PMCID: PMC3937304 DOI: 10.1371/journal.ppat.1003930] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 01/02/2014] [Indexed: 12/19/2022] Open
Abstract
Human lymphatic filariasis is a major tropical disease transmitted through mosquito vectors which take up microfilarial larvae from the blood of infected subjects. Microfilariae are produced by long-lived adult parasites, which also release a suite of excretory-secretory products that have recently been subject to in-depth proteomic analysis. Surprisingly, the most abundant secreted protein of adult Brugia malayi is triose phosphate isomerase (TPI), a glycolytic enzyme usually associated with the cytosol. We now show that while TPI is a prominent target of the antibody response to infection, there is little antibody-mediated inhibition of catalytic activity by polyclonal sera. We generated a panel of twenty-three anti-TPI monoclonal antibodies and found only two were able to block TPI enzymatic activity. Immunisation of jirds with B. malayi TPI, or mice with the homologous protein from the rodent filaria Litomosoides sigmodontis, failed to induce neutralising antibodies or protective immunity. In contrast, passive transfer of neutralising monoclonal antibody to mice prior to implantation with adult B. malayi resulted in 60–70% reductions in microfilarial levels in vivo and both oocyte and microfilarial production by individual adult females. The loss of fecundity was accompanied by reduced IFNγ expression by CD4+ T cells and a higher proportion of macrophages at the site of infection. Thus, enzymatically active TPI plays an important role in the transmission cycle of B. malayi filarial parasites and is identified as a potential target for immunological and pharmacological intervention against filarial infections. Triose phosphate isomerase (TPI) is a ubiquitous and highly conserved enzyme in intracellular glucose metabolism. Surprisingly, the human lymphatic filariai nematode parasite Brugia malayi, releases TPI into the extracellular environment, suggesting a role in helminth survival in the mammalian host. We first established that B. malayi-infected humans and rodents generate TPI-specific serum antibody responses, confirming presentation of this protein to the host immune system. However, immunisation of rodents with B. malayi TPI did not induce protection against infection. Furthermore, TPI from a related parasite, Litomosoides sigmodontis, did not induce protective immunity in mice. Notably, antibodies from infected hosts did not neutralise the enzymatic activity of TPI. We then generated twenty-three anti-TPI monoclonal antibodies, of which only two inhibited enzymatic activity. Transfer of neutralising antibody to mice prior to B. malayi infection effected a 69.5% reduction in microfilarial levels in vivo and a 60% reduction in microfilariae produced by individual adult female parasites. Corresponding shifts in the host immune response included reduced Th1 cytokine production and enhanced macrophage numbers. Enzymatically active TPI therefore promotes production of the transmission stage of B. malayi filarial parasites and represents a rational target for new vaccine and drug development to protect against filarial infections.
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Affiliation(s)
- James P. Hewitson
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Dominik Rückerl
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Yvonne Harcus
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Janice Murray
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Lauren M. Webb
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Simon A. Babayan
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Judith E. Allen
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Agnes Kurniawan
- Department of Parasitology, University of Indonesia, Jakarta, Indonesia
| | - Rick M. Maizels
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
- * E-mail:
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Zhao L, Zhang S, Wei W, Hao H, Zhang B, Butcher RA, Sun J. Chemical signals synchronize the life cycles of a plant-parasitic nematode and its vector beetle. Curr Biol 2013; 23:2038-43. [PMID: 24120638 DOI: 10.1016/j.cub.2013.08.041] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Revised: 05/13/2013] [Accepted: 08/12/2013] [Indexed: 01/24/2023]
Abstract
The pinewood nematode Bursaphelenchus xylophilus has caused severe damage to pine forests in large parts of the world [1-4]. Dispersal of this plant-parasitic nematode occurs when the nematode develops into the dispersal fourth larval stage (LIV) upon encountering its insect vector, the Monochamus pine sawyer beetle, inside an infected pine tree [5-9]. Here, we show that LIV formation in B. xylophilus is induced by C16 and C18 fatty acid ethyl esters (FAEEs), which are produced abundantly on the body surface of the vector beetle specifically during the late development pupal, emerging adult, and newly eclosed adult stages. The LIV can then enter the tracheal system of the adult beetle for dispersal to a new pine tree. Treatment of B. xylophilus with long-chain FAEEs, or the PI3 kinase inhibitor LY294002, promotes LIV formation, while Δ7-dafachronic acid blocks the effects of these chemicals, suggesting a conserved role for the insulin/IGF-1 and DAF-12 pathways in LIV formation. Our work provides a mechanism by which LIV formation in B. xylophilus is specifically coordinated with the life cycle of its vector beetle. Knowledge of the chemical signals that control the LIV developmental decision could be used to interfere with the dispersal of this plant-parasitic nematode.
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Affiliation(s)
- Lilin Zhao
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China; Department of Chemistry, University of Florida, Gainesville, FL 32611, USA
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The dauer hypothesis and the evolution of parasitism: 20 years on and still going strong. Int J Parasitol 2013; 44:1-8. [PMID: 24095839 DOI: 10.1016/j.ijpara.2013.08.004] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 08/19/2013] [Accepted: 08/21/2013] [Indexed: 01/31/2023]
Abstract
How any complex trait has evolved is a fascinating question, yet the evolution of parasitism among the nematodes is arguably one of the most arresting. How did free-living nematodes cross that seemingly insurmountable evolutionary chasm between soil dwelling and survival inside another organism? Which of the many finely honed responses to the varied and harsh environments of free-living nematodes provided the material upon which natural selection could act? Although several complementary theories explain this phenomenon, I will focus on the dauer hypothesis. The dauer hypothesis posits that the arrested third-stage dauer larvae of free-living nematodes such as Caenorhabditis elegans are, due to their many physiological similarities with infective third-stage larvae of parasitic nematodes, a pre-adaptation to parasitism. If so, then a logical extension of this hypothesis is that the molecular pathways which control entry into and recovery from dauer formation by free-living nematodes in response to environmental cues have been co-opted to control the processes of infective larval arrest and activation in parasitic nematodes. The molecular machinery that controls dauer entry and exit is present in a wide range of parasitic nematodes. However, the developmental outputs of the different pathways are both conserved and divergent, not only between populations of C. elegans or between C. elegans and parasitic nematodes but also between different species of parasitic nematodes. Thus the picture that emerges is more nuanced than originally predicted and may provide insights into the evolution of such an interesting and complex trait.
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40
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Hewitson JP, Ivens AC, Harcus Y, Filbey KJ, McSorley HJ, Murray J, Bridgett S, Ashford D, Dowle AA, Maizels RM. Secretion of protective antigens by tissue-stage nematode larvae revealed by proteomic analysis and vaccination-induced sterile immunity. PLoS Pathog 2013; 9:e1003492. [PMID: 23966853 PMCID: PMC3744408 DOI: 10.1371/journal.ppat.1003492] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 05/28/2013] [Indexed: 11/30/2022] Open
Abstract
Gastrointestinal nematode parasites infect over 1 billion humans, with little evidence for generation of sterilising immunity. These helminths are highly adapted to their mammalian host, following a developmental program through successive niches, while effectively down-modulating host immune responsiveness. Larvae of Heligmosomoides polygyrus, for example, encyst in the intestinal submucosa, before emerging as adult worms into the duodenal lumen. Adults release immunomodulatory excretory-secretory (ES) products, but mice immunised with adult H. polygyrus ES become fully immune to challenge infection. ES products of the intestinal wall 4th stage (L4) larvae are similarly important in host-parasite interactions, as they readily generate sterile immunity against infection, while released material from the egg stage is ineffective. Proteomic analyses of L4 ES identifies protective antigen targets as well as potential tissue-phase immunomodulatory molecules, using as comparators the adult ES proteome and a profile of H. polygyrus egg-released material. While 135 proteins are shared between L4 and adult ES, 72 are L4 ES-specific; L4-specific proteins correspond to those whose transcription is restricted to larval stages, while shared proteins are generally transcribed by all life cycle forms. Two protein families are more heavily represented in the L4 secretome, the Sushi domain, associated with complement regulation, and the ShK/SXC domain related to a toxin interfering with T cell signalling. Both adult and L4 ES contain extensive but distinct arrays of Venom allergen/Ancylostoma secreted protein-Like (VAL) members, with acetylcholinesterases (ACEs) and apyrase APY-3 particularly abundant in L4 ES. Serum antibodies from mice vaccinated with L4 and adult ES react strongly to the VAL-1 protein and to ACE-1, indicating that these two antigens represent major vaccine targets for this intestinal nematode. We have thus defined an extensive and novel repertoire of H. polygyrus proteins closely implicated in immune modulation and protective immunity. Intestinal helminth parasites are highly prevalent in humans and animals, and survive for long periods by deviating the host immune system. No vaccines are currently available to control these infections. Many helminths invade through barrier surfaces (such as the skin or the digestive tract) and develop through tissue larval stages before reaching their final niche such as the intestinal lumen. We studied the tissue larval stage of a mouse parasite, Heligmosomoides polygyrus, to test whether proteins released by this stage could elicit protective immunity, and found that they indeed constitute very effective vaccine antigens. Proteomic analysis to identify the individual proteins released by the larvae demonstrated that while many products are shared between tissue-dwelling larvae and adults occupying the intestinal lumen, larvae express higher levels of two gene families linked to immunomodulation, namely the Sushi protein family and the ShK toxin family. Antibody analysis of serum from vaccinated mice identified two major antigens recognised by the protective immune response as VAL-1 and ACE-1, which are respectively members of the venom allergen and acetylcholinesterase families. This work establishes that tissue larvae are the source of protective antigens for future vaccines, and highlights their production of two potentially immunomodulatory gene families.
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MESH Headings
- Animals
- Antibodies, Helminth/analysis
- Antibodies, Helminth/immunology
- Antigens, Helminth/immunology
- Antigens, Helminth/metabolism
- Blotting, Western
- Chromatography, Liquid
- Computational Biology
- Electrophoresis, Gel, Two-Dimensional
- Enzyme-Linked Immunosorbent Assay
- Female
- Gene Expression Profiling
- Helminth Proteins/immunology
- Helminth Proteins/metabolism
- Host-Parasite Interactions
- Immunization
- Immunoprecipitation
- Larva/immunology
- Larva/metabolism
- Mice
- Mice, Inbred C57BL
- Mice, Inbred CBA
- Nematode Infections/immunology
- Nematode Infections/parasitology
- Nematospiroides dubius/growth & development
- Nematospiroides dubius/immunology
- Proteomics
- Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
- Vaccination
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Affiliation(s)
- James P. Hewitson
- Institute of Immunology and Infection Research, Ashworth Laboratories, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Al C. Ivens
- Centre for Immunity, Infection and Evolution, Ashworth Laboratories, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Yvonne Harcus
- Institute of Immunology and Infection Research, Ashworth Laboratories, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Kara J. Filbey
- Institute of Immunology and Infection Research, Ashworth Laboratories, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Henry J. McSorley
- Institute of Immunology and Infection Research, Ashworth Laboratories, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Janice Murray
- Institute of Immunology and Infection Research, Ashworth Laboratories, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Stephen Bridgett
- Gene Pool, Ashworth Laboratories, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - David Ashford
- Technology Facility, University of York, York, United Kingdom
| | - Adam A. Dowle
- Technology Facility, University of York, York, United Kingdom
| | - Rick M. Maizels
- Institute of Immunology and Infection Research, Ashworth Laboratories, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
- * E-mail:
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41
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Nisbet AJ, McNeilly TN, Wildblood LA, Morrison AA, Bartley DJ, Bartley Y, Longhi C, McKendrick IJ, Palarea-Albaladejo J, Matthews JB. Successful immunization against a parasitic nematode by vaccination with recombinant proteins. Vaccine 2013; 31:4017-23. [DOI: 10.1016/j.vaccine.2013.05.026] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Revised: 04/16/2013] [Accepted: 05/08/2013] [Indexed: 10/26/2022]
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Thivierge K, Cotton S, Schaefer DA, Riggs MW, To J, Lund ME, Robinson MW, Dalton JP, Donnelly SM. Cathelicidin-like helminth defence molecules (HDMs): absence of cytotoxic, anti-microbial and anti-protozoan activities imply a specific adaptation to immune modulation. PLoS Negl Trop Dis 2013; 7:e2307. [PMID: 23875042 PMCID: PMC3708846 DOI: 10.1371/journal.pntd.0002307] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Accepted: 05/29/2013] [Indexed: 11/19/2022] Open
Abstract
Host defence peptides (HDPs) are expressed throughout the animal and plant kingdoms. They have multifunctional roles in the defence against infectious agents of mammals, possessing both bactericidal and immune-modulatory activities. We have identified a novel family of molecules secreted by helminth parasites (helminth defence molecules; HDMs) that exhibit similar structural and biochemical characteristics to the HDPs. Here, we have analyzed the functional activities of four HDMs derived from Schistosoma mansoni and Fasciola hepatica and compared them to human, mouse, bovine and sheep HDPs. Unlike the mammalian HDPs the helminth-derived HDMs show no antimicrobial activity and are non-cytotoxic to mammalian cells (macrophages and red blood cells). However, both the mammalian- and helminth-derived peptides suppress the activation of macrophages by microbial stimuli and alter the response of B cells to cytokine stimulation. Therefore, we hypothesise that HDMs represent a novel family of HDPs that evolved to regulate the immune responses of their mammalian hosts by retaining potent immune modulatory properties without causing deleterious cytotoxic effects. In mammals, secreted host defence peptides (HDPs) protect against a wide range of infectious pathogens. They also perform a range of immune modulatory functions which regulate the immune response to pathogens, ensuring that the protective inflammatory response is not exacerbated and that post-infection repair mechanisms are initiated. We identified a novel family of molecules secreted by medically-important helminth pathogens (termed helminth defence molecules; HDMs) that exhibit striking structural and biochemical similarities to the HDPs. To further investigate the extent of this similarity, we have performed a comparative functional study between several well characterized, anti-microbial, mammalian HDPs and a series of parasite-derived peptides. The parasite HDMs displayed immune modulatory properties that were similar to their HDP homologs in mammals, but possessed no antimicrobial or cytotoxic activity. We propose that HDMs of these helminth pathogens underwent specific adaptation, losing their anti-microbial activity but retaining their ability to regulate the immune responses of their mammalian hosts. This absence of cytotoxicity and retention of immune-modulatory activity offers an opportunity to design novel immunotherapeutics derived from the HDMs which could be used to combat destructive inflammatory responses associated with microbial infection and immune-related disorders.
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Affiliation(s)
- Karine Thivierge
- Institute of Parasitology, McGill University, Sainte-Anne-de-Bellevue, Quebec, Canada
- Laboratoire de Santé Publique du Québec, Institut National de Santé Publique du Québec, Sainte-Anne-de-Bellevue, Quebec, Canada
| | - Sophie Cotton
- Institute of Parasitology, McGill University, Sainte-Anne-de-Bellevue, Quebec, Canada
| | - Deborah A. Schaefer
- Department of Veterinary Science and Microbiology, University of Arizona, Tucson, Arizona, United States of America
| | - Michael W. Riggs
- Department of Veterinary Science and Microbiology, University of Arizona, Tucson, Arizona, United States of America
| | - Joyce To
- The ithree Institute, University of Technology Sydney (UTS), Sydney, Australia
| | - Maria E. Lund
- The ithree Institute, University of Technology Sydney (UTS), Sydney, Australia
| | - Mark W. Robinson
- The ithree Institute, University of Technology Sydney (UTS), Sydney, Australia
- School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, Belfast, Northern Ireland
| | - John P. Dalton
- Institute of Parasitology, McGill University, Sainte-Anne-de-Bellevue, Quebec, Canada
| | - Sheila M. Donnelly
- The ithree Institute, University of Technology Sydney (UTS), Sydney, Australia
- * E-mail:
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43
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Abstract
Transforming Growth Factor-β (TGF-β) superfamily ligands regulate many aspects of cell identity, function, and survival in multicellular animals. Genes encoding five TGF-β family members are present in the genome of C. elegans. Two of the ligands, DBL-1 and DAF-7, signal through a canonical receptor-Smad signaling pathway; while a third ligand, UNC-129, interacts with a noncanonical signaling pathway. No function has yet been associated with the remaining two ligands. Here we summarize these signaling pathways and their biological functions.
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Affiliation(s)
- Tina L Gumienny
- Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX 77843, USA
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44
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Reynolds LA, Filbey KJ, Maizels RM. Immunity to the model intestinal helminth parasite Heligmosomoides polygyrus. Semin Immunopathol 2012; 34:829-46. [PMID: 23053394 PMCID: PMC3496515 DOI: 10.1007/s00281-012-0347-3] [Citation(s) in RCA: 164] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2012] [Accepted: 09/13/2012] [Indexed: 02/07/2023]
Abstract
Heligmosomoides polygyrus is a natural intestinal parasite of mice, which offers an excellent model of the immunology of gastrointestinal helminth infections of humans and livestock. It is able to establish long-term chronic infections in many strains of mice, exerting potent immunomodulatory effects that dampen both protective immunity and bystander reactions to allergens and autoantigens. Immunity to the parasite develops naturally in some mouse strains and can be induced in others through immunization; while the mechanisms of protective immunity are not yet fully defined, both antibodies and a host cellular component are required, with strongest evidence for a role of alternatively activated macrophages. We discuss the balance between resistance and susceptibility in this model system and highlight new themes in innate and adaptive immunity, immunomodulation, and regulation of responsiveness in helminth infection.
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Affiliation(s)
- Lisa A. Reynolds
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, EH9 3JT UK
| | - Kara J. Filbey
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, EH9 3JT UK
| | - Rick M. Maizels
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, EH9 3JT UK
- Institute of Immunology and Infection Research, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JT UK
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Stoltzfus JD, Minot S, Berriman M, Nolan TJ, Lok JB. RNAseq analysis of the parasitic nematode Strongyloides stercoralis reveals divergent regulation of canonical dauer pathways. PLoS Negl Trop Dis 2012; 6:e1854. [PMID: 23145190 PMCID: PMC3493385 DOI: 10.1371/journal.pntd.0001854] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Accepted: 08/26/2012] [Indexed: 01/25/2023] Open
Abstract
The infectious form of many parasitic nematodes, which afflict over one billion people globally, is a developmentally arrested third-stage larva (L3i). The parasitic nematode Strongyloides stercoralis differs from other nematode species that infect humans, in that its life cycle includes both parasitic and free-living forms, which can be leveraged to investigate the mechanisms of L3i arrest and activation. The free-living nematode Caenorhabditis elegans has a similar developmentally arrested larval form, the dauer, whose formation is controlled by four pathways: cyclic GMP (cGMP) signaling, insulin/IGF-1-like signaling (IIS), transforming growth factor β (TGFβ) signaling, and biosynthesis of dafachronic acid (DA) ligands that regulate a nuclear hormone receptor. We hypothesized that homologous pathways are present in S. stercoralis, have similar developmental regulation, and are involved in L3i arrest and activation. To test this, we undertook a deep-sequencing study of the polyadenylated transcriptome, generating over 2.3 billion paired-end reads from seven developmental stages. We constructed developmental expression profiles for S. stercoralis homologs of C. elegans dauer genes identified by BLAST searches of the S. stercoralis genome as well as de novo assembled transcripts. Intriguingly, genes encoding cGMP pathway components were coordinately up-regulated in L3i. In comparison to C. elegans, S. stercoralis has a paucity of genes encoding IIS ligands, several of which have abundance profiles suggesting involvement in L3i development. We also identified seven S. stercoralis genes encoding homologs of the single C. elegans dauer regulatory TGFβ ligand, three of which are only expressed in L3i. Putative DA biosynthetic genes did not appear to be coordinately regulated in L3i development. Our data suggest that while dauer pathway genes are present in S. stercoralis and may play a role in L3i development, there are significant differences between the two species. Understanding the mechanisms governing L3i development may lead to novel treatment and control strategies. Parasitic nematodes infect over one billion people worldwide and cause many diseases, including strongyloidiasis, filariasis, and hookworm disease. For many of these parasites, including Strongyloides stercoralis, the infectious form is a developmentally arrested and long-lived thirdstage larva (L3i). Upon encountering a host, L3i quickly resume development and mature into parasitic adults. In the free-living nematode Caenorhabditis elegans, a similar developmentally arrested third-stage larva, known as the dauer, is regulated by four key cellular mechanisms. We hypothesized that similar cellular mechanisms control L3i arrest and activation. Therefore, we used deep-sequencing technology to characterize the S. stercoralis transcriptome (RNAseq), which allowed us to identify S. stercoralis homologs of components of these four mechanisms and examine their temporal regulation. We found similar temporal regulation between S. stercoralis and C. elegans for components of two mechanisms, but dissimilar temporal regulation for two others, suggesting conserved as well as novel modes of developmental regulation for L3i. Understanding L3i development may lead to novel control strategies as well as new treatments for strongyloidiasis and other diseases caused by parasitic nematodes.
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Affiliation(s)
- Jonathan D. Stoltzfus
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America
| | - Samuel Minot
- Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Matthew Berriman
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom
| | - Thomas J. Nolan
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America
| | - James B. Lok
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America
- * E-mail:
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McSorley HJ, O'Gorman MT, Blair N, Sutherland TE, Filbey KJ, Maizels RM. Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminth Heligmosomoides polygyrus. Eur J Immunol 2012; 42:2667-82. [PMID: 22706967 PMCID: PMC4916998 DOI: 10.1002/eji.201142161] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2011] [Revised: 05/11/2012] [Accepted: 06/06/2012] [Indexed: 01/23/2023]
Abstract
Allergic asthma is less prevalent in countries with parasitic helminth infections, and mice infected with parasites such as Heligmosomoides polygyrus are protected from allergic airway inflammation. To establish whether suppression of allergy could be mediated by soluble products of this helminth, we tested H. polygyrus excretory-secretory (HES) material for its ability to impair allergic inflammation. When HES was added to sensitising doses of ovalbumin, the subsequent allergic airway response was suppressed, with ablated cell infiltration, a lower ratio of effector (CD4(+) CD25(+) Foxp3(-) ) to regulatory (CD4(+) Foxp3(+) ) T (Treg) cells, and reduced Th1, Th2 and Th17 cytokine production. HES exposure reduced IL-5 responses and eosinophilia, abolished IgE production and inhibited the type 2 innate molecules arginase-1 and RELM-α (resistin-like molecule-α). Although HES contains a TGF-β-like activity, similar effects in modulating allergy were not observed when administering mammalian TGF-β alone. HES also protected previously sensitised mice, suppressing recruitment of eosinophils to the airways when given at challenge, but no change in Th or Treg cell populations was apparent. Because heat-treatment of HES did not impair suppression at sensitisation, but compromised its ability to suppress at challenge, we propose that HES contains distinct heat-stable and heat-labile immunomodulatory molecules, which modulate pro-allergic adaptive and innate cell populations.
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Affiliation(s)
| | | | | | | | | | - Rick M Maizels
- Institute of Immunology and Infection Research University of Edinburgh, Edinburgh, EH9 3JT, UK
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Maizels RM, Hewitson JP, Murray J, Harcus YM, Dayer B, Filbey KJ, Grainger JR, McSorley HJ, Reynolds LA, Smith KA. Immune modulation and modulators in Heligmosomoides polygyrus infection. Exp Parasitol 2012; 132:76-89. [PMID: 21875581 PMCID: PMC6485391 DOI: 10.1016/j.exppara.2011.08.011] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2011] [Revised: 08/09/2011] [Accepted: 08/15/2011] [Indexed: 01/12/2023]
Abstract
The intestinal nematode parasite Heligmosomoides polygyrus bakeri exerts widespread immunomodulatory effects on both the innate and adaptive immune system of the host. Infected mice adopt an immunoregulated phenotype, with abated allergic and autoimmune reactions. At the cellular level, infection is accompanied by expanded regulatory T cell populations, skewed dendritic cell and macrophage phenotypes, B cell hyperstimulation and multiple localised changes within the intestinal environment. In most mouse strains, these act to block protective Th2 immunity. The molecular basis of parasite interactions with the host immune system centres upon secreted products termed HES (H. polygyrus excretory-secretory antigen), which include a TGF-β-like ligand that induces de novo regulatory T cells, factors that modify innate inflammatory responses, and molecules that block allergy in vivo. Proteomic and transcriptomic definition of parasite proteins, combined with biochemical identification of immunogenic molecules in resistant mice, will provide new candidate immunomodulators and vaccine antigens for future research.
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Affiliation(s)
- Rick M Maizels
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3JT, UK.
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Nono JK, Pletinckx K, Lutz MB, Brehm K. Excretory/secretory-products of Echinococcus multilocularis larvae induce apoptosis and tolerogenic properties in dendritic cells in vitro. PLoS Negl Trop Dis 2012; 6:e1516. [PMID: 22363826 PMCID: PMC3283565 DOI: 10.1371/journal.pntd.0001516] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2011] [Accepted: 12/19/2011] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Alveolar echinococcosis, caused by Echinococcus multilocularis larvae, is a chronic disease associated with considerable modulation of the host immune response. Dendritic cells (DC) are key effectors in shaping the immune response and among the first cells encountered by the parasite during an infection. Although it is assumed that E.multilocularis, by excretory/secretory (E/S)-products, specifically affects DC to deviate immune responses, little information is available on the molecular nature of respective E/S-products and their mode of action. METHODOLOGY/PRINCIPAL FINDINGS We established cultivation systems for exposing DC to live material from early (oncosphere), chronic (metacestode) and late (protoscolex) infectious stages. When co-incubated with Echinococcus primary cells, representing the invading oncosphere, or metacestode vesicles, a significant proportion of DC underwent apoptosis and the surviving DC failed to mature. In contrast, DC exposed to protoscoleces upregulated maturation markers and did not undergo apoptosis. After pre-incubation with primary cells and metacestode vesicles, DC showed a strongly impaired ability to be activated by the TLR ligand LPS, which was not observed in DC pre-treated with protoscolex E/S-products. While none of the larvae induced the secretion of pro-inflammatory IL-12p70, the production of immunosuppressive IL-10 was elevated in response to primary cell E/S-products. Finally, upon incubation with DC and naïve T-cells, E/S-products from metacestode vesicles led to a significant expansion of Foxp3+ T cells in vitro. CONCLUSIONS This is the first report on the induction of apoptosis in DC by cestode E/S-products. Our data indicate that the early infective stage of E. multilocularis is a strong inducer of tolerance in DC, which is most probably important for generating an immunosuppressive environment at an infection phase in which the parasite is highly vulnerable to host attacks. The induction of CD4+CD25+Foxp3+ T cells through metacestode E/S-products suggests that these cells fulfill an important role for parasite persistence during chronic echinococcosis.
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Affiliation(s)
- Justin Komguep Nono
- University of Würzburg, Institute of Hygiene and Microbiology, Würzburg, Germany
| | - Katrien Pletinckx
- University of Würzburg, Institute of Virology and Immunobiology, Würzburg, Germany
| | - Manfred B. Lutz
- University of Würzburg, Institute of Virology and Immunobiology, Würzburg, Germany
| | - Klaus Brehm
- University of Würzburg, Institute of Hygiene and Microbiology, Würzburg, Germany
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Hewitson JP, Harcus Y, Murray J, van Agtmaal M, Filbey KJ, Grainger JR, Bridgett S, Blaxter ML, Ashton PD, Ashford DA, Curwen RS, Wilson RA, Dowle AA, Maizels RM. Proteomic analysis of secretory products from the model gastrointestinal nematode Heligmosomoides polygyrus reveals dominance of venom allergen-like (VAL) proteins. J Proteomics 2011; 74:1573-94. [PMID: 21722761 DOI: 10.1016/j.jprot.2011.06.002] [Citation(s) in RCA: 124] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2011] [Revised: 05/20/2011] [Accepted: 06/05/2011] [Indexed: 01/25/2023]
Abstract
The intestinal helminth parasite, Heligmosomoides polygyrus bakeri offers a tractable experimental model for human hookworm infections such as Ancylostoma duodenale and veterinary parasites such as Haemonchus contortus. Parasite excretory-secretory (ES) products represent the major focus for immunological and biochemical analyses, and contain immunomodulatory molecules responsible for nematode immune evasion. In a proteomic analysis of adult H. polygyrus secretions (termed HES) matched to an extensive transcriptomic dataset, we identified 374 HES proteins by LC-MS/MS, which were distinct from those in somatic extract HEx, comprising 446 identified proteins, confirming selective export of ES proteins. The predominant secreted protein families were proteases (astacins and other metalloproteases, aspartic, cysteine and serine-type proteases), lysozymes, apyrases and acetylcholinesterases. The most abundant products were members of the highly divergent venom allergen-like (VAL) family, related to Ancylostoma secreted protein (ASP); 25 homologues were identified, with VAL-1 and -2 also shown to be associated with the parasite surface. The dominance of VAL proteins is similar to profiles reported for Ancylostoma and Haemonchus ES products. Overall, this study shows that the secretions of H. polygyrus closely parallel those of clinically important GI nematodes, confirming the value of this parasite as a model of helminth infection.
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Affiliation(s)
- James P Hewitson
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3JT, UK
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A calcium-activated nucleotidase secreted from Ostertagia ostertagi 4th-stage larvae is a member of the novel salivary apyrases present in blood-feeding arthropods. Parasitology 2011; 138:333-43. [PMID: 20809998 DOI: 10.1017/s0031182010001241] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Apyrases (ATP-diphosphohydrolase) comprise a ubiquitous class of glycosylated nucleotidases that hydrolyse extracellular ATP and ADP to orthophosphate and AMP. One class of newly-described, Ca2+-dependent, salivary apyrases known to counteract blood-clotting, has been identified in haematophagous arthropods. Herein, we have identified a gene (Oos-apy-1) encoding a protein that structurally conforms to the Ca2+-activated apyrase from the bed bug, Cimex lectularius, by immunologically screening an Ostertagia L4 cDNA expression library. The expressed protein (rOos-APY-1) was biochemically functional in the presence of Ca2+ only, with greatest activity on ATP, ADP, UTP and UDP. Host antibodies to the fusion protein appeared as early as 14 days post-infection (p.i.) and increased through 30 days p.i. Immunohistochemical and Western blot analyses demonstrated that the native Oos-APY-1 protein is present in the glandular bulb of the oesophagus and is confined to the L4. A putative signal sequence at the N-terminus and near 100% identity with a Teladorsagia circumcincta L4 secreted protein is consistent with the native protein being secreted at the cellular level. Predicated upon substrate specificity, the native protein may be used by the parasite to control the levels of host extracellular nucleotides released by locally-damaged tissues in an effort to modulate immune intervention and inflammation.
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