Biology subjects

Harnett, W.

Publications and source records attributed to Harnett, W..

3 recordsLinked to original sources

bioRxiv2020

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

The parasitic worm product, ES-62 protects against collagen-induced arthritis, a mouse model of rheumatoid arthritis (RA) by suppressing the synovial fibroblast (SF) responses perpetuating inflammation and driving joint destruction. Such SF responses are shaped during disease progression by the inflammatory microenvironment of the joint that promotes remodelling of their epigenetic landscape, inducing an "aggressive" pathogenic SF phenotype. Critically, exposure to ES-62 in vivo induces a stably imprinted "safe" phenotype that exhibits responses more typical of healthy SFs. Surprisingly however, DNA methylome analysis reveals that rather than simply preventing the pathogenic rewiring of SFs, ES-62 induces further epigenetic remodelling, including targeting genes associated with ciliogenesis and differentiation, to program a distinct "protective" phenotype. Such unique behaviour signposts potential DNA methylation signatures predictive of pathogenesis and its resolution and hence, candidate mechanisms by which novel therapeutic interventions could prevent SFs from perpetuating joint inflammation and destruction in RA.

pathology↗

bioRxiv2019

Parasitic worm product ES-62 promotes healthspan and lifespan in a mouse model of obesity-induced ageing

The recent extension of human lifespan has not been matched by equivalent improvements in late-life health due to the global pandemic in type-2 diabetes, obesity and cardiovascular disease, ageing-associated conditions exacerbated by widespread adoption of the high calorie Western diet (HCD). As a novel therapeutic strategy, we have investigated the potential of ES-62, an immunomodulator secreted by the parasitic worm Acanthocheilonema viteae, to improve healthspan by targeting the chronic inflammation that drives metabolic dysregulation underpinning ageing-induced ill-health. We found that ES-62 improves a range of inflammatory but also pathophysiological, metabolic and microbiome parameters, when administered subcutaneously at only 1 {micro}g/week throughout the lifespan of HCD-fed mice. Strikingly, ES-62 induced sex-specific healthspan signatures and indeed, it substantially increased the median survival of male, but not female, HCD-mice. Modelling of 113 responses contributing to these differential signatures by machine learning approaches now signposts candidate parameters key to promoting both healthspan and lifespan.

immunology↗

bioRxiv2018

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

The human immune system has evolved in the context of our colonisation by bacteria, viruses, fungi and parasitic helminths. Reflecting this, the rapid eradication of pathogens appears to have resulted in reduced microbiome diversity and generation of chronically activated immune systems, presaging the recent rise of allergic, autoimmune and metabolic disorders. Certainly, gastrointestinal helminths can protect against gut and lung mucosa inflammatory conditions by modulating the microbiome and suppressing the chronic inflammation associated with dysbiosis. Here, we employ ES-62, an immunomodulator secreted by tissue-dwelling Acanthocheilonema viteae to show that modulation of the gut microbiome does not require live infection with gastrointestinal-based helminths nor is protection restricted to mucosal diseases. Specifically, subcutaneous administration of this defined parasitic worm product affords protection against joint disease in collagen-induced arthritis, a mouse model of rheumatoid arthritis, which is associated with normalisation of gut microbiota and prevention of loss of intestinal barrier integrity.

immunology↗