The parasitic worm-derived immunomodulator, ES-62 and its drug-like small molecule analogues exhibit therapeutic potential in a model of chronic asthma

Abstract

Chronic asthma is associated with persistent lung inflammation and long-term remodelling of the airways that have proved refractory to conventional treatments such as steroids, despite their efficacy in controlling acute airway contraction and bronchial inflammation. As its recent dramatic increase in industrialised countries has not been mirrored in developing regions, it has been suggested that helminth infection may protect humans against developing asthma. Consistent with this, ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, can prevent pathology associated with chronic asthma (cellular infiltration of the lungs, particularly neutrophils and mast cells, mucus hyper-production and airway thickening) in an experimental mouse model. Importantly, ES-62 can act even after airway remodelling has been established, arresting pathogenesis and ameliorating the inflammatory flares resulting from repeated exposure to allergen that are a debilitating feature of severe chronic asthma. Moreover, two chemical analogues of ES-62, 11a and 12b mimic its therapeutic actions in restoring levels of regulatory B cells and suppressing neutrophil and mast cell responses. These studies therefore provide a platform for developing ES-62-based drugs, with compounds 11a and 12b representing the first step in the development of a novel class of drugs to combat the hitherto intractable disorder of chronic asthma.

The helminth product, ES-62 modulates dendritic cell responses by inducing the selective autophagolysosomal degradation of TLR-transducers, as exemplified by PKCδ

“…ES-62 is a PC-containing immunomodulatory glycoprotein that exhibits protective effects in models of allergic and autoimmune disease911 by homeostatically resetting the effector: regulatory B cell balance and consequently modulating the IL-23/IL-17/IL-22 inflammatory axis2345630, dysregulation of which has been implicated in the pathogenesis of chronic inflammatory disorders31. Although the precise cellular networks modulated by the worm product appear to differ depending on the inflammatory context, ES-62 likely affords protection by acting to subvert TLR signalling via partial downregulation of MyD88 expression in effector cells of both innate and adaptive immunity346917.…”

“…Although the precise cellular networks modulated by the worm product appear to differ depending on the inflammatory context, ES-62 likely affords protection by acting to subvert TLR signalling via partial downregulation of MyD88 expression in effector cells of both innate and adaptive immunity346917. The effect of targeting this key integrator of inflammatory signalling is exemplified by the ability of ES-62 to suppress both the priming and maintenance of pathogenic Th17 and IL-17-producing γδ T cells in CIA by targeting MyD88 in both DCs and Th17 cells49.…”

“…We have previously shown that ES-62, a phosphorylcholine (PC)-containing immunomodulatory glycoprotein secreted by the filarial nematode Acanthocheilonema viteae , is protective in mouse models of allergic123 and autoimmune456 disease. Such protection is associated with homeostatic resetting of the IL-23/IL-17/IL-22 inflammatory axis, which appears to become dysregulated in these inflammatory disorders: a key effector driving development of this type of inflammation is the dendritic cell (DC), which ES-62 targets by subverting TLR4 signalling789 to suppress aberrant DC-priming of Th17 cells and IL-17-producing γδ T cells24.…”

The parasitic worm product ES-62 promotes health- and life-span in a high calorie diet-accelerated mouse model of ageing

“…We have previously shown that a single, defined ES protein, ES-62, can resolve chronic inflammation by normalising aberrant MyD88 signalling to homeostatically restore immunoregulation, irrespective of the inflammatory phenotype [4,5,[10][11][12]. MyD88 is increasingly recognized not only as a key innate immune system receptor transducer but also as an integrator of dysregulated inflammatory and metabolic pathways [7,[13][14][15].…”

The parasitic worm product ES-62 normalises the gut microbiota/bone marrow axis in inflammatory arthritis

“…Amongst the best characterised ES products is ES-62, a phosphorylcholine (PC)-containing glycoprotein secreted by the rodent filarial nematode Acanthocheilonema viteae that we have shown to prevent initiation and progression of pathology in mouse models of certain allergic (asthma, contact dermatitis) and autoimmune (RA, SLE) inflammatory diseases 1,2,[38][39][40][41][42][43] . Collectively, our studies have identified a unifying mechanism of action that allows effective protection irrespective of the inflammatory phenotype: thus, by subverting TLR4 signalling to downregulate aberrant MyD88-responses, ES-62 acts to homeostatically reset the regulatory:effector immune cell balance, primarily to restore levels of IL-10 + regulatory B cells (Bregs) and suppress pathological IL-17-driven inflammation 1,2,[38][39][40][41][42][43][44] . In experimental models of RA and human disease, perturbation of the microbiota has been shown to disrupt the balance of pathogenic Th17 cells and the counter-regulatory Bregs and Tregs that act to homeostatically resolve inflammation 20,[24][25][26] .…”