ES-62, a therapeutic anti-inflammatory agent evolved by the filarial nematode Acanthocheilonema viteae

Pineda, Miguel A.; Lumb, Felicity E.; Harnett, Margaret M.; Harnett, William

doi:10.1016/j.molbiopara.2014.03.003

Cited by 77 publications

(72 citation statements)

References 56 publications

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“…El-Sadr et al (1983) showed that canine neutrophils and PBMCs would adhere to, and the neutrophils could kill, D. immitis Mf with the help of IgM from occultly infected animal serum. Parasitic nematodes, including the filaria, secrete a cocktail of immunomodulatory proteins, metabolites and microRNAs which have significant effects on the host immune system (Ashour 2013; Harnett 2014; Harnett and Harnett 2006; Hoerauf et al 2005; McSorley et al 2013; Pineda et al 2014; Wang et al 2014; Buck et al 2014), so it is an obvious speculation that they act to inhibit granulocyte and PBMC binding and antibody-dependent killing of Mf in the infected animal. Another important drug used in the LF elimination programme, diethylcarbamizine (DEC), is believed to exert its anthelmintic effects via activation of the host immune system (Maizels and Denham 1992; Vickery et al 1985), which is consistent with its limited direct effects on nematodes in vitro (Alves et al 2005; Court et al 1986; Gunawardena et al 2005).…”

Section: Is the Host Immune System Involved?mentioning

confidence: 99%

How do the macrocyclic lactones kill filarial nematode larvae?

Wolstenholme¹,

MacLean²,

Coates

et al. 2016

Invert Neurosci

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The macrocyclic lactones (MLs) are one of the few classes of drug used in the control of the human filarial infections, onchocerciasis and lymphatic filariasis, and the only one used to prevent heartworm disease in dogs and cats. Despite their importance in preventing filarial diseases, the way in which the MLs work against these parasites is unclear. In vitro measurements of nematode motility have revealed a large discrepancy between the maximum plasma concentrations achieved after drug administration and the amounts required to paralyze worms. Recent evidence has shed new light on the likely functions of the ML target, glutamate-gated chloride channels, in filarial nematodes and supports the hypothesis that the rapid clearance of microfilariae that follows treatment involves the host immune system.

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Section: Is the Host Immune System Involved?mentioning

confidence: 99%

How do the macrocyclic lactones kill filarial nematode larvae?

Wolstenholme¹,

MacLean²,

Coates

et al. 2016

Invert Neurosci

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“…Thus, therapeutic intervention by applying defined helminth-secreted immunomodulators may represent a targeted strategy to treat inflammatory responses; indeed, excretory/secretory components of nematode parasites have been shown to efficiently suppress inflammation in experimental models (reviewed in Refs. 1,4). Our previous studies showed that cystatin from the filarial roundworm Acanthocheilonema viteae (AvCystatin) is a potent immunomodulator (5,6) that protects mice against OVA-induced airway inflammation in a macrophage-and IL-10-dependent manner (7).…”

mentioning

confidence: 99%

A Novel Regulatory Macrophage Induced by a Helminth Molecule Instructs IL-10 in CD4+ T Cells and Protects against Mucosal Inflammation

Ziegler

Rausch

Steinfelder

et al. 2015

The Journal of Immunology

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Immunomodulation is a common feature of chronic helminth infections and mainly attributed to the secretion of bioactive molecules, which target and modify host immune cells. In this study, we show that the helminth immunomodulator AvCystatin, a cysteine protease inhibitor, induces a novel regulatory macrophage (Mreg; AvCystatin-Mreg), which is sufficient to mitigate major parameters of allergic airway inflammation and colitis in mice. A single adoptive transfer of AvCystatin-Mreg before allergen challenge suppressed allergen-specific IgE levels, the influx of eosinophils into the airways, local and systemic Th2 cytokine levels, and mucus production in lung bronchioles of mice, whereas increasing local and systemic IL-10 production by CD4+ T cells. Moreover, a single administration of AvCystatin-Mreg during experimentally induced colitis strikingly reduced intestinal pathology. Phenotyping of AvCystatin-Mreg revealed increased expression of a distinct group of genes including LIGHT, sphingosine kinase 1, CCL1, arginase-1, and costimulatory molecules, CD16/32, ICAM-1, as well as PD-L1 and PD-L2. In cocultures with dendritic cells and CD4+ T cells, AvCystatin-Mreg strongly induced the production of IL-10 in a cell-contact–independent manner. Collectively, our data identify a specific suppressive macrophage population induced by a single parasite immunomodulator, which protects against mucosal inflammation.

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“…Structural analysis of the molecule revealed the attachment of phosphorylcholine (PC) to an N -type glycan, a post-translational modification not previously described (Houston and Harnett, 2004). The PC moiety confers a wide range of immunomodulatory properties on ES-62, which are broadly anti-inflammatory in nature (Harnett et al, 2003; Pineda et al, 2014). As a consequence, ES-62 is able to inhibit inflammatory responses and thus protect against the development of disease in mouse models of arthritis and asthma (McInnes et al, 2003; Melendez et al, 2007).…”

mentioning

confidence: 99%

The immunomodulatory parasitic worm product ES-62 reduces lupus-associated accelerated atherosclerosis in a mouse model

Aprahamian

Zhong

Amir

et al. 2015

International Journal for Parasitology

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ES-62 is an anti-inflammatory phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae. Accelerated atherosclerosis frequently occurs in systemic lupus erythematosus (SLE), resulting in substantial cardiovascular morbidity and mortality. We examined the effects of ES-62 in the gld.apoE−/− mouse model of this condition. Treatment with ES-62 did not substantially modulate renal pathology but caused decreased anti-nuclear autoantibody levels. Moreover, a striking 60% reduction in aortic atherosclerotic lesions was observed, with an associated decrease in macrophages and fibrosis. We believe that these latter findings constitute the first example of a defined parasitic worm product with therapeutic potential in atherosclerosis: ES-62-based drugs may represent a novel approach to control accelerated atherosclerosis in SLE.

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ES-62, a therapeutic anti-inflammatory agent evolved by the filarial nematode Acanthocheilonema viteae

Cited by 77 publications

References 56 publications

How do the macrocyclic lactones kill filarial nematode larvae?

How do the macrocyclic lactones kill filarial nematode larvae?

A Novel Regulatory Macrophage Induced by a Helminth Molecule Instructs IL-10 in CD4+ T Cells and Protects against Mucosal Inflammation

The immunomodulatory parasitic worm product ES-62 reduces lupus-associated accelerated atherosclerosis in a mouse model

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