Publications
72 results found
Roberts L, Berkachy R, Wane M, et al., 2022, Differential regulation of allergic airway inflammation by acetylcholine, Frontiers in Immunology, Vol: 13, ISSN: 1664-3224
Acetylcholine (ACh) from neuronal and non-neuronal sources plays important roles in the regulation of immune responses and is associated with the development of several disease pathologies. We have previously demonstrated that group 2 innate lymphoid cell (ILC2)-derived ACh is required for optimal type 2 responses to parasitic infection, and therefore sought to determine whether this also plays a role in allergic inflammation. RoraCre+ChatLoxP mice (in which ILC2s cannot synthesize ACh) were exposed to an allergenic extract of the fungus Alternaria alternata, and immune responses in the airways and lung tissues analysed. Airway neutrophilia and expression of the neutrophil chemoattractants CXCL1 and CXCL2 were enhanced 24 hours after exposure, suggesting that ILC2-derived ACh plays a role in limiting excessive pulmonary neutrophilic inflammation. The effect of non-selective depletion of ACh was examined by intranasal administration of a stable parasite-secreted acetylcholinesterase. Depletion of airway ACh in this manner resulted in more profound enhancement of neutrophilia and chemokine expression, suggesting multiple cellular sources for release of ACh. In contrast, depletion of ACh inhibited Alternaria-induced activation of ILC2s, suppressing expression of IL-5, IL-13 and subsequent eosinophilia. Depletion of ACh resulted in a reduction of macrophages with an alternatively activated M2 phenotype, and an increase in M1 macrophage marker expression. These data suggest that ACh regulates allergic airway inflammation in several ways, enhancing ILC2-driven eosinophilia, but suppressing neutrophilia through reduced chemokine expression.
Roberts LB, Schnoeller C, Berkachy R, et al., 2021, Acetylcholine production by group 2 innate lymphoid cells promotes mucosal immunity to helminths, Science Immunology, Vol: 6, ISSN: 2470-9468
Innate lymphoid cells (ILCs) are critical mediators of immunological and physiological responses at mucosal barrier sites. Whereas neurotransmitters can stimulate ILCs, the synthesis of small-molecule neurotransmitters by these cells has only recently been appreciated. Group 2 ILCs (ILC2s) are shown here to synthesize and release acetylcholine (ACh) during parasitic nematode infection. The cholinergic phenotype of pulmonary ILC2s was associated with their activation state, could be induced by in vivo exposure to extracts of Alternaria alternata or the alarmin cytokines interleukin-33 (IL-33) and IL-25, and was augmented by IL-2 in vitro. Genetic disruption of ACh synthesis by murine ILC2s resulted in increased parasite burdens, lower numbers of ILC2s, and reduced lung and gut barrier responses to Nippostrongylus brasiliensis infection. These data demonstrate a functional role for ILC2-derived ACh in the expansion of ILC2s for maximal induction of type 2 immunity.
Berkachy R, Smyth DJ, Schnoeller C, et al., 2021, Characterisation of the secreted apyrase family of Heligmosomoides polygyrus, International Journal for Parasitology, Vol: 51, Pages: 39-48, ISSN: 0020-7519
Apyrases are a recurrent feature of secretomes from numerous species of parasitic nematodes. Here we characterise the five apyrases secreted by Heligmosomoides polygyrus, a natural parasite of mice and a widely used laboratory model for intestinal nematode infection. All five enzymes are closely related to soluble calcium-activated nucleotidases described in a variety of organisms, and distinct from the CD39 family of ecto-nucleotidases. Expression is maximal in adult worms and restricted to adults and L4s. Recombinant apyrases were produced and purified from Pichia pastoris. The five enzymes showed very similar biochemical properties, with strict calcium dependence and a broad substrate specificity, catalysing the hydrolysis of all nucleoside tri- and diphosphates, with no activity against nucleoside monophosphates. Natural infection of mice provoked very low antibodies to any enzyme, but immunisation with an apyrase cocktail showed partial protection against reinfection, with reduced egg output and parasite recovery. The most likely role for nematode secreted apyrases is hydrolysis of extracellular ATP, which acts as an alarmin for cellular release of IL-33 and initiation of type 2 immunity.
Selkirk ME, Davis RE, Gounaris K, et al., 2018, Special issue: molecular and cellular biology of helminth parasites XI Preface, International Journal for Parasitology, Vol: 48, Pages: 319-320, ISSN: 0020-7519
Vaux R, Schnoeller C, Berkachy R, et al., 2016, Modulation of the immune response by nematode secreted acetylcholinesterase revealed by heterologous expression in Trypanosoma musculi, PLOS Pathogens, Vol: 12, Pages: 1-18, ISSN: 1553-7366
Nematode parasites secrete molecules which regulate the mammalian immune system, but their genetic intractability is a major impediment to identifying and characterising the biological effects of these molecules. We describe here a novel system for heterologous expression of helminth secreted proteins in the natural parasite of mice, Trypanosoma musculi, which can be used to analyse putative immunomodulatory functions. Trypanosomes were engineered to express a secreted acetylcholinesterase from Nippostrongylus brasiliensis. Infection of mice with transgenic parasites expressing acetylcholinesterase resulted in truncated infection, with trypanosomes cleared early from the circulation. Analysis of cellular phenotypes indicated that exposure to acetylcholinesterase in vivo promoted classical activation of macrophages (M1), with elevated production of nitric oxide and lowered arginase activity. This most likely occurred due to the altered cytokine environment, as splenocytes from mice infected with T. musculi expressing acetylcholinesterase showed enhanced production of IFNγ and TNFα, with diminished IL-4, IL-13 and IL-5. These results suggest that one of the functions of nematode secreted acetylcholinesterase may be to alter the cytokine environment in order to inhibit development of M2 macrophages which are deleterious to parasite survival. Transgenic T. musculi represents a valuable new vehicle to screen for novel immunoregulatory proteins by extracellular delivery in vivo to the murine host.
Rashidi NM, Scott MK, Scherf N, et al., 2014, In vivo time-lapse imaging shows diverse niche engagement by quiescent and naturally activated hematopoietic stem cells, BLOOD, Vol: 124, Pages: 79-83, ISSN: 0006-4971
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- Citations: 49
Afferson HC, Eleftheriou E, Selkirk ME, et al., 2012, Trichinella spiralis secreted enzymes regulate nucleotide-induced mast cell activation and release of mouse mast cell protease-1, Infection and Immunity, Vol: 80, Pages: 3761-3767
White RR, Miyata S, Papa E, et al., 2011, Characterisation of the Trichinella spiralis deubiquitinating enzyme, TsUCH37, an evolutionarily conserved proteasome interaction partner., PLoS Neglected Tropical Diseases, Vol: 5
Rees-Roberts D, Mullen LM, Gounaris K, et al., 2010, Inactivation of the complement anaphylatoxin C5a by secreted products of parasitic nematodes, INTERNATIONAL JOURNAL FOR PARASITOLOGY, Vol: 40, Pages: 527-532, ISSN: 0020-7519
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- Citations: 17
Huang SCC, Chan DTY, Smyth DJ, et al., 2010, Activation of Nippostrongylus brasiliensis infective larvae is regulated by a pathway distinct from the hookworm Ancylostoma caninum., International Journal for Parasitology, Vol: 40, Pages: 1619-1628
Huang SCC, Chan DTY, Smyth DJ, et al., 2010, Activation of Nippostrongylus brasiliensis infective larvae is regulated by a pathway distinct from the hookworm Ancylostoma caninum, Int J Parasitol, Vol: in press
Guiliano DB, Oksov Y, Lustigman S, et al., 2009, Characterisation of novel protein families secreted by muscle stage larvae of <i>Trichinella spiralis</i>, INTERNATIONAL JOURNAL FOR PARASITOLOGY, Vol: 39, Pages: 515-524, ISSN: 0020-7519
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- Citations: 12
Selkirk ME, Gounaris K, 2006, Analysis of helminth immunomodulatory molecules by RNA interference, PARASITE IMMUNOLOGY, Vol: 28, Pages: 263-263, ISSN: 0141-9838
Bruce AF, Gares M-P, Selkirk ME, et al., 2006, Functional characterisation of a nematode secreted GM2-activator protein, MOLECULAR AND BIOCHEMICAL PARASITOLOGY, Vol: 147, Pages: 224-229, ISSN: 0166-6851
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- Citations: 9
Bruce AF, Gounaris K, 2006, Characterisation of a secreted N-acetyl-β-hexosaminidase from <i>Trichinella spiralis</i>, MOLECULAR AND BIOCHEMICAL PARASITOLOGY, Vol: 145, Pages: 84-93, ISSN: 0166-6851
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- Citations: 15
Guiliano DB, Gounaris K, Selkirk ME, 2005, Identification of potential mediators of nurse cell transformation from <i>Trichinella Spiralis</i>, AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, Vol: 73, Pages: 336-337, ISSN: 0002-9637
Kock S, Gounaris K, 2005, Proteins secreted by <i>Trichinella Spiralis</i> alter nucleotide-induced migration of dendritic cells, AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, Vol: 73, Pages: 336-336, ISSN: 0002-9637
Gounaris K, Selkirk ME, 2005, Parasite nucleotide-metabolizing enzymes and host purinergic signalling, TRENDS IN PARASITOLOGY, Vol: 21, Pages: 17-21, ISSN: 1471-4922
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- Citations: 38
Gounaris K, Selkirk ME, Sadeghi SJ, 2004, A nucleotidase with unique catalytic properties is secreted by <i>Trichinella spiralis</i>, MOLECULAR AND BIOCHEMICAL PARASITOLOGY, Vol: 136, Pages: 257-264, ISSN: 0166-6851
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- Citations: 25
Selkirk ME, Hussein AS, Chambers AE, et al., 2004, <i>Trichinella spiralis</i> secretes a homologue of prosaposin, MOLECULAR AND BIOCHEMICAL PARASITOLOGY, Vol: 135, Pages: 49-56, ISSN: 0166-6851
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- Citations: 11
Selkirk ME, Gounaris K, 2004, Adaptations of parasitic nematodes to mammalian host immunity, 4th International Nematology Congress, Publisher: BRILL, Pages: 589-600, ISSN: 1573-5869
Gounaris K, 2002, Nucleotidase cascades are catalyzed by secreted proteins of the parasitic nematode <i>Trichinella spiralis</i>, INFECTION AND IMMUNITY, Vol: 70, Pages: 4917-4924, ISSN: 0019-9567
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- Citations: 46
Gounaris K, Thomas S, Najarro P, et al., 2001, Secreted variant of nucleoside diphosphate kinase from the intracellular parasitic nematode <i>Trichinella spiralis</i>, INFECTION AND IMMUNITY, Vol: 69, Pages: 3658-3662, ISSN: 0019-9567
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- Citations: 44
Smith VP, Selkirk ME, Gounaris K, 2000, A reversible protein phosphorylation system is present at the surface of infective larvae of the parasitic nematode <i>Trichinella spiralis</i>, FEBS LETTERS, Vol: 483, Pages: 104-108, ISSN: 0014-5793
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- Citations: 18
Selkirk ME, Smith VP, Thomas GR, et al., 1998, Resistance of filarial nematode parasites to oxidative stress, INTERNATIONAL JOURNAL FOR PARASITOLOGY, Vol: 28, Pages: 1315-1332, ISSN: 0020-7519
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- Citations: 102
Smith VP, Selkirk ME, Gounaris K, 1998, <i>Brugia malayi</i>:: Resistance of cuticular lipids to oxidant-induced damage and detection of α-tocopherol in the neutral lipid fraction, EXPERIMENTAL PARASITOLOGY, Vol: 88, Pages: 103-110, ISSN: 0014-4894
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- Citations: 17
Arden SR, Smith AM, Booth MJ, et al., 1997, Identification of serine/threonine protein kinase secreted by <i>Trichinella spiralis</i> infective larvae, MOLECULAR AND BIOCHEMICAL PARASITOLOGY, Vol: 90, Pages: 111-119, ISSN: 0166-6851
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- Citations: 34
Smith VP, Selkirk ME, Gounaris K, 1996, Brugia malayi: Ultrastructural morphology of the cuticular surface membranes of adult parasites, EXPERIMENTAL PARASITOLOGY, Vol: 83, Pages: 304-313, ISSN: 0014-4894
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- Citations: 3
Grigg ME, Gounaris K, Selkirk ME, 1996, Characterization of a platelet-activating factor acetylhydrolase secreted by the nematode parasite Nippostrongylus brasiliensis, BIOCHEMICAL JOURNAL, Vol: 317, Pages: 541-547, ISSN: 0264-6021
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- Citations: 17
Smith VP, Selkirk ME, Gounaris K, 1996, Identification and composition of lipid classes in surface and somatic preparations of adult Brugia malnyi, MOLECULAR AND BIOCHEMICAL PARASITOLOGY, Vol: 78, Pages: 105-116, ISSN: 0166-6851
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- Citations: 17
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