Employing parasitic worm products to improve healing of chronic wounds

Abstract

Diabetic chronic wounds impose a substantial burden on both the individual and the healthcare system. Pathogenesis of chronic wounds is linked to an excessive inflammatory response, involving increased macrophage retention and a disrupted macrophage phenotype. Manipulation of wound macrophages through the use of immunomodulatory molecules is an attractive therapeutic option. Helminths are able to manipulate the host’s immune response through the production of excretory/secretory (ES) products. Indeed, ES administration has been linked to therapeutic benefit in a number of inflammatory conditions. However, their use in the treatment of excessively inflammatory chronic wounds remains to be explored. Utilising murine models of wounding and helminth infection (Heligmosomoides polygyrus bakeri) the results presented in this thesis describe a mechanism of compartmentalised systemic immune education occurring during H. polygyrus infection. Type 2 education is restricted to mucosal barrier sites, whilst IFN-g education occurs almost ubiquitously. Education in this manner enables the host to be concurrently protected against further helminth infection and circulating bacterial challenge whilst allowing monocytes recruited to the wound bed to acquire a pro- healing (RELMa+) phenotype. Application of H. polygyrus ES to the wound throughout healing induces a similar RELMa+ phenotype in wound monocytes and macrophages. Indeed, through application of in vitro and in vivo models of wound repair and inflammation, data presented here identifies the ability of H. polygyrus ES to modulate both keratinocyte and macrophage functions, two cell populations central in mediating successful wound closure. Specifically, ES treatment has a suppressive effect on macrophage responses to stimuli and accelerates keratinocyte migration in an in vitro scratch wound model. Taken together, this work highlights H. polygyrus ES as a potentially exciting option in the treatment of inflammatory chronic wounds. H. polygyrus ES is capable of modulating the functions of two fundamental cell populations: keratinocytes and macrophages. Further research is required to identify the specific ES molecules responsible for mediating the described effects in order to fully exploit H. polygyrus ES’s therapeutic potential.

Date of Award	1 Aug 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Kathryn Else (Supervisor), Nicola Tirelli (Supervisor), Kimberly Mace (Supervisor) & John Grainger (Supervisor)