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Acanthocheilonema viteae

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Heiko Apfel – One of the best experts on this subject based on the ideXlab platform.

William Harnett – One of the best experts on this subject based on the ideXlab platform.

  • Synthetic small molecule analogues of the immunomodulatory Acanthocheilonema viteae product ES-62 promote metabolic homeostasis during obesity in a mouse model.
    Molecular and biochemical parasitology, 2019
    Co-Authors: Felicity E. Lumb, Margaret M. Harnett, James Doonan, Colin J. Suckling, Jenny Crowe, Colin Selman, William Harnett
    Abstract:

    Abstract One of the most rapidly increasing human public health problems is obesity, whose sequelae like type-2 diabetes, represent continuously worsening, life-long conditions. Over the last 15 years, data have begun to emerge from human and more frequently, mouse studies, that support the idea that parasitic worm infection can protect against this condition. We have therefore investigated the potential of two synthetic small molecule analogues (SMAs) of the anti-inflammatory Acanthocheilonema viteae product ES-62, to protect against metabolic dysfunction in a C57BL/6 J mouse model of high calorie diet-induced obesity. We found weekly subcutaneous administration of the SMAs in combination (1 μg of each), starting one week before continuous exposure to high calorie diet (HCD), decreased fasting glucose levels and reversed the impaired glucose clearance observed in male mice, when measured at approximately 7 and 13 weeks after exposure to HCD. Fasting glucose levels were also-reduced in male mice fed a HCD for some 38 weeks when given SMA-treatment 13 weeks after the start of HCD, indicating an SMA-therapeutic potential. For the most part, protective effects were not observed in female mice. SMA treatment also conferred protection against each of reduced ileum villus length and liver fibrfibrosis, but more prominently in female mice. Previous studies in mice indicate that protection against metabolic dysfunction is usually associated with polarisation of the immune system towards a type-2/anti-inflammatory direction but our attempts to correlate improved metabolic parameters with such changes were unsuccessful. Further analysis will therefore be required to define mechanism of action. Nevertheless, overall our data clearly show the potential of the drug-like SMAs as a preventative or treatment for metabolic dysregulation associated with obesity.

  • Testing small molecule analogues of the Acanthocheilonema viteae immunomodulator ES-62 against clinically relevant allergens.
    Parasite immunology, 2016
    Co-Authors: Lucia Janicova, Margaret M. Harnett, Justyna Rzepecka, David T. Rodgers, James Doonan, Kara S. Bell, Felicity E. Lumb, Colin J. Suckling, William Harnett
    Abstract:

    ES-62 is a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae that protects against ovalbumin (OVA)-induced airway hyper-responsiveness in mice by virtue of covalently attached anti-inflammatory phosphorylcholine (PC) residues. We have recently generated a library of Small Molecule Analogues (SMAs) of ES-62 based around its active PC moiety as a starting point in novel drug development for asthma, and isolated two compounds – termed 11a and 12b – that mirror ES-62’s protective effects. In the present study we have moved away from OVA, a model allergen, to test the two SMAs against two clinically relevant allergens – house dust mite (HDM) and cockroach allergen (CR) extract. We show that whereas both SMAs offer some protection against development of lung allergic responses to CR, in particular reducing eosinophil infiltration, only SMA 12b is effective in protecting against eosinophil-dependent HDM-induced allergy. These data therefore suggest that helminth molecule-induced protection against model antigens may not necessarily translate to clinically relevant antigens. Nevertheless, in the present study we have managed to demonstrate that it is possible to produce synthetic drug-like molecules based on a parasitic worm product that show therapeutic potential with respect to asthma resulting from known triggers in humans.

  • Protective effect of small molecule analogues of the Acanthocheilonema viteae secreted product ES-62 on oxazolone-induced ear inflammation
    Experimental parasitology, 2015
    Co-Authors: Lamyaa Al-riyami, Margaret M. Harnett, Miguel A Pineda, Justyna Rzepecka, David T. Rodgers, Colin J. Suckling, William Harnett
    Abstract:

    ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following their administration before oxazolone sensitisation and before oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered before challenge. Histological analysis of the ears showed elevated cellular infiinfiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNγ mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed.

R K Chatterjee – One of the best experts on this subject based on the ideXlab platform.

Claus T. Lattemann – One of the best experts on this subject based on the ideXlab platform.

  • up regulation of extracellular copper zinc superoxide dismutase mrna after transmission of the filarial parasite Acanthocheilonema viteae in the vertebrate host meriones unguiculatus
    International Journal for Parasitology, 1999
    Co-Authors: Claus T. Lattemann, Arne Matzen, Heiko Apfel
    Abstract:

    Abstract The gene encoding the cytoplasmic copper/zinc superoxide dismutase (AVSOD1) from the filarial parasite Acanthocheilonema viteae was isolated from a genomic DNA library using a degenerate oligonucleotide probe. Additionally, cDNAs of the AVSOD1 and the secreted extracellular SOD (AVSOD2) were both cloned by RT–PCR, and the AVSOD2 was expressed at high levels in E. coli . The amino acid sequence of the AVSOD1 is 89.5 and 87.5% identical to that of the corresponding enzymes of Brugia pahangi and Onchocerca volvulus , respectively. In contrast, the AVSOD2 shows a lower degree of identity to the other filarial SODs and is extensively glycosylated. RT–PCR studies demonstrate the expression of both SOD subtypes in all developmental stages of A. viteae and indicate up-regulation of the AVSOD2 expression after transmission from the vector to the definitive host. This suggests an enhanced requirement for SOD activity in post-infective larval stages and adults of A. viteae . ELISAs performed with purified recombinant AVSOD2 show that the AVSOD2 is not a major target for the immune system in naturally infected jirds.

  • immunogenicity of the extracellular copper zinc superoxide dismutase of the filarial parasite Acanthocheilonema viteae delivered by a two phase vaccine strain of salmonella typhimurium
    Parasite Immunology, 1999
    Co-Authors: Claus T. Lattemann, Thomas F. Meyer, Zhengxin Yan, Arne Matzen, Heiko Apfel
    Abstract:

    The recombinant extracellular copper/zinc superoxide dismutase of the filarial parasite Acanthocheilonema viteae (AVSOD2) was cloned in an expression vector under control of the bacteriophage T7 promoter and the resulting plasmid pLAT7 was introduced in tha aroA attenuated Salmonella typhimurium vaccine strain SL3261::pYZ84. This vaccine strain carries a chromosomally integrated two phase expression system containing inducible T7 RNA polymerase. The recombinant AVSOD2 was efficiently expressed, constituting up to 5% of the total bacterial protein. Furthermore, the plasmid vector containing the AVSOD2 cDNA was shown to be stable over a long period of time in the vaccine strain without antibiotic selection in vitro and in vivo. Jirds which were immunised orally with the recombinant vaccine strain expressing the A. viteae EC-SOD produced a strong humoral immune response.

  • Immunogenicity of the extracellular copper/zinc superoxide dismutase of the filarial parasite Acanthocheilonema viteae delivered by a two-phase vaccine strain of Salmonella typhimurium
    Parasite immunology, 1999
    Co-Authors: Claus T. Lattemann, Thomas F. Meyer, Zhengxin Yan, Arne Matzen, Heiko Apfel
    Abstract:

    The recombinant extracellular copper/zinc superoxide dismutase of the filarial parasite Acanthocheilonema viteae (AVSOD2) was cloned in an expression vector under control of the bacteriophage T7 promoter and the resulting plasmid pLAT7 was introduced in tha aroA attenuated Salmonella typhimurium vaccine strain SL3261::pYZ84. This vaccine strain carries a chromosomally integrated two phase expression system containing inducible T7 RNA polymerase. The recombinant AVSOD2 was efficiently expressed, constituting up to 5% of the total bacterial protein. Furthermore, the plasmid vector containing the AVSOD2 cDNA was shown to be stable over a long period of time in the vaccine strain without antibiotic selection in vitro and in vivo. Jirds which were immunised orally with the recombinant vaccine strain expressing the A. viteae EC-SOD produced a strong humoral immune response.

Richard Lucius – One of the best experts on this subject based on the ideXlab platform.

  • Modelling and simulating interleukin-10 production and regulation by macrophages after stimulation with an immunomodulator of parasitic nematodes.
    The FEBS journal, 2009
    Co-Authors: Ana Sofia Figueiredo, Richard Lucius, Susanne Hartmann, Thomas Höfer, Christian Klotz, Christine Sers, Peter Hammerstein
    Abstract:

    Parasitic nematodes can downregulate the immune response of their hosts through the induction of immunoregulatory cytokines such as interleukin-10 (IL-10). To define the underlying mechanisms, we measured in vitro the production of IL-10 in macrophages in response to cystatin from Acanthocheilonema viteae, an immunomodulatory protein of filarial nematodes, and developed mathematical models of IL-10 regulation. IL-10 expression requires stimulation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and p38, and we propose that a negative feedfeedback mechanism, acting at the signalling level, is responsible for transient IL-10 production that can be followed by a sustained plateau. Specifically, a model with negative feedback on the ERK pathway via secreted IL-10 accounts for the experimental data. Accordingly, the model predicts sustained phospho-p38 dynamics, whereas ERK activation changes from transient to sustained when the concentration of immunomodulatory protein of Acanthocheilonema viteae increases. We show that IL-10 can regulate its own production in an autocrine fashion, and that ERK and p38 control IL-10 amplitude, duration and steady state. We also show that p38 affects ERK via secreted IL-10 (autocrine crosstalk). These findings demonstrate how convergent signalling pathways may differentially control kinetic properties of the IL-10 signal.

  • Essential Role of Chitinase in the Development of the Filarial Nematode Acanthocheilonema viteae
    Infection and immunity, 2007
    Co-Authors: Babila Tachu, Richard Lucius, Smitha P. S. Pillai, Thomas Pogonka
    Abstract:

    Chitinases of pathogens have been proposed as potential targets of vaccines or specific inhibitors. We studied the genomic organization, transcript levels, developmental expression, and biological function of chitinases in the rodent filarial nematode Acanthocheilonema viteae, a model organism for human-pathogenic filarial worms. Characterization of nine genomic clones from an A. viteae phage library and Southern blot experiments revealed the existence of three different chitinase genes, two of which could theoretically yield functional transcripts. The deduced proteins of these genes had the common modular organization of family 18 chitinases. Northern blot experiments and rapid amplification of cDNA ends-PCR with adult worms and larval stages showed that only one gene is expressed, with high variation in transcript levels, as determined by real-time PCR. Chitinase transcript levels were lowest in the late male stage 4 larva (L4) and peaked in the stage 3 larva (L3), which was corroborated by Western blotting. RNA interference (RNAi) experiments showed that treatment of L3 and adult female worms with double-stranded RNA of chitinase inhibited molting of L3 worms and hatching of microfilariae. RNAi also led to the death of 50% of female worms, revealing the essential role of chitinase in the life cycle of filarial nematodes.

  • A nematode allergen elicits protection against challenge infection under specific conditions.
    Vaccine, 2006
    Co-Authors: Susanne Hartmann, Michal J. Sereda, Andre Sollwedel, Bernd H. Kalinna, Richard Lucius
    Abstract:

    Abstract We describe tropomyosin of the filarial nematode Acanthocheilonema viteae as an allergen and study its protective potential in the natural rodent host Meriones unguiculatus (jird). Jirds immunized with recombinant E. coli -expressed A . viteae tropomyosin emusified in alum were not protected, while immunization with recombinant A . viteae tropomyosin or with protein purified from worms together with the adjuvant STP led to reduction of adult worm burdens by 30%. Vaccination with cDNA induced protection of about 30%, while application of cDNA together with aluminium phosphosphate increased the protection to >40%. Our data suggest that vaccination with tropomyosin under Th1 conditions, which are untypical for nematode infections, induces protection via an antibody independent effector mechanism.