Publications

Reduction in creatine metabolites in macrophages exposed to small molecule analogues of the anti-inflammatory parasitic worm product ES-62

Alanazi S, Doonan J, Lumb F E, Alenzi N, Jabbar S, Al-Riyami L, Suckling C J, Harnett W, Watson D G

Parasite Immunology Vol 46 (2024)

https://doi.org/10.1111/pim.13026

Epigenetic changes induced by parasitic worms and their excretory-secretory products

Harnett William, Harnett Margaret M

Biochemical Society Transactions Vol 52, pp. 55–63 (2024)

https://doi.org/10.1042/BST20230087

The parasitic worm product ES- 62 protects against collageninduced arthritis by resetting the gut-bone marrow axis in a microbiome-dependent manner

Harnett Margaret, Doonan James, Tarafdar Anuradha, Pineda Miguel, Duncombe-Moore Josephine, Buitrago Geraldine, Pan Piaopiao, Hoskisson Paul, Selman Colin, Harnett William

Frontiers in Tropical Diseases Vol 4 (2024)

https://doi.org/10.3389/fitd.2023.1334705

Protection against lung pathology during obesity-accelerated ageing in mice by the parasitic worm product ES-62

Harnett Margaret M, Lumb Felicity E, Crowe Jenny, Doonan James, Buitrago Geraldine, Brown Stephanie, Thom Gillian, MacDonald Amy, Suckling Colin J, Selman Colin, Harnett William

Frontiers in Immunology Vol 14 (2023)

https://doi.org/10.3389/fimmu.2023.1285069

Do parasitic worm products reverse endothelial dysfunction in cerebral small vessel disease?

Lumbreras Perales Cristina, Suckling Colin, Scott Fraser, Harnett William, Van Agtmael Tom, Carswell Hilary

6th UK Preclinical Stroke Symposium 2023 (2023)

The therapeutic potential of drug-like small molecule analogues of the parasitic worm product ES-62 in cerebral small vessel disease

Lumbreras Perales Cristina, Harnett William, Suckling Colin, Scott Fraser, Van Agtmael Tom, Carswell Hilary

6th UK Preclinical Stroke Symposium 2023 (2023)

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Professional Activities

Molecular and Cellular Biology of Helminth Parasites IX

Speaker

30/8/2015

Molecular and Cellular Biology of Helminth Parasites IX

Chair

30/8/2015

The parasitic worm product ES-62: a starting point for novel anti-inflammatory drug development

Invited speaker

25/8/2015

Infection and Immunity (Journal)

Editorial board member

1/1/2015

International Filariasis Meeting

Invited speaker

26/9/2014

International Filariasis Meeting

Chair

26/9/2014

More professional activities

Projects

How does the immunomodulatory parasitic worm product ES-62 rewire bone marrow cells to increase healthspan and lifespan in obesity-accelerated ageing?

Harnett, William (Principal Investigator) Hoskisson, Paul (Co-investigator)

01-Jun-2021 - 31-Dec-2024

Does the parasitic worm product ES-62 resolve aberrant chronic inflammation by sensing and normalising the gut microbiome and intestinal integrity?

Harnett, William (Principal Investigator) Hoskisson, Paul (Co-investigator)

10-May-2021 - 31-Oct-2024

Efficacy of small molecule analogues of the anti-inflammatory parasitic worm product, ES-62, in protecting against stroke

Carswell, Hilary (Principal Investigator) Harnett, William (Co-investigator)

01-Oct-2020 - 31-Jan-2025

Can studying the mechanism of action of the parasitic worm-derived immunomodulator ES-62, inform on how to slow ageing and improve healthspan?

Harnett, William (Principal Investigator)

"The introduction of vaccines and drugs to control disease, in combination with greater access to food and improved sanitation, means that people are now living much longer. Currently this increase is staggering, equating to an extra 2.5 years of life per decade. However, improved life expectancy itself amounts to a huge new problem, in that it is not being accompanied by a similar increase in health and wellbeing. This reflects both that like a mechanical machine such as a car engine, the ageing process is naturally associated with a loss of function of its systems due to wear and tear, but also that improved wealth has resulted in a modern Western life-style, incorporating a high fat diet (HFD) that contributes to age-associated ailments such as type-2 diabetes (T2D), stroke and heart disease. This impact of increased lifespan presenting with associated ill-health has enormous socio-economic implications due to its increasingly global scale, arguing for a need to better understand the process of ageing in the context of health.

Approximately one quarter of the world's population is infected with parasitic worms. Of interest, several recent reports indicate that such infections offer protection against development of conditions such as obesity, cardiovascular disease and T2D in mouse models and that similar protection may also be seen in humans. We have been studying one individual parasitic worm component - ES-62, isolated from the secretory products of the filarial nematode, Acanthocheilonema viteae, and consistent with these studies, ES-62 is highly effective in reducing the cardiovascular disease that arises in a highly susceptible strain of mouse, particularly in response to a high fat diet. Moreover, we have some preliminary data showing that ES-62 may offer some protection against development of the obesity that is associated with development of T2D.

Our studies to date with ES-62 also show it to be effective in inhibiting the development of disease in mouse models of allergy, rheumatoid arthritis and systemic lupus erythematosus. What all of these diseases have in common with cardiovascular disease and T2D is the increasing realization that they are associated with unwanted inflammation. This immediately offers an explanation for ES-62's protective effects, as the parasitic worm-derived molecule possesses a range of anti-inflammatory properties. Furthermore, as ageing is also now being considered as a biological problem in the setting of chronic low-grade inflammation, this raises the possibility of investigating the effect of ES-62 on the ageing process and late-life health and well being (healthspan). Thus, we specifically plan to determine whether ES-62 can slow ageing and improve healthspan using a paradigm where mice will be fed on a high fat diet +/- ES-62. We will use this model to assess the effect of ES-62 treatment on ageing in the context of promotion of gene signatures and signalling pathways known to be associated with ageing/inflammation versus those associated with longevity and healthspan.

In addition to enabling us to establish whether ES-62's anti-inflammatory properties are impacting on the ageing process at the molecular level as predicted, this strategy might allow us to validate novel biomarkers for ageing and even potential sites of therapeutic intervention. With respect to the latter, we have produced synthetic drug-like small molecule analogues (SMAs) of ES-62 during our work on the allergy and autoimmunity models, with a view to using these as a starting point in novel drug development for these conditions. Thus, although the current application is designed to increase understanding of the biology of ageing rather than drug development, we will conduct a small trial with one of these SMAs towards the final year of the project with a view to submitting future grant applications for impact funding for their development as potential therapies."

01-Feb-2016 - 31-Jul-2019

MIMIC - Do parasitic worms and their secreted immunomudulators protect against musculosketal disease by impacting on the host microbiome?

Harnett, William (Principal Investigator) Hoskisson, Paul (Co-investigator)

MIMIC - Do parasitic worms and their secreted immunomudulators protect against musculosketal disease by impacting on the host microbiome?

01-Oct-2015 - 30-Jun-2018

Using C. elegans to produce proteins from parasitic nematodes for research and therapeutic use

Harnett, William (Principal Investigator)

01-Jan-2014 - 30-Jun-2014

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