Modulation of macrophage metabolism and function by the helminth peptide FhHDM-1

Loli Quinteros, Susel Mayra

Modulation of macrophage metabolism and function by the helminth peptide FhHDM-1

Loli Quinteros, Susel Mayra

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Publication Type:: Thesis
Issue Date:: 2023

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Field	Value	Language
dc.contributor.author	Loli Quinteros, Susel Mayra
dc.date.accessioned	2024-03-26T00:04:31Z
dc.date.available	2024-03-26T00:04:31Z
dc.date.issued	2023
dc.identifier.uri	http://hdl.handle.net/10453/177148
dc.description	University of Technology Sydney. Faculty of Science.	en_US.UTF-8
dc.description.abstract	Parasitic worms have evolved sophisticated strategies to regulate their host’s immune response, to prevent expulsion and establish chronic infections. Understanding how they achieve this offers a therapeutic strategy for the treatment of human diseases which are caused by unregulated inflammation. Previous characterisation of the liver fluke’s secreted proteins identified a peptide (termed FhHDM-1) that inhibited progression of immune-mediated disease in murine models of diabetes, multiple sclerosis and asthma. The aim of this PhD project was to uncover the mechanisms by which FhHDM-1 was mediating this beneficial effect. The research discovered that FhHDM-1 peptide regulates inflammation by reprogramming macrophage metabolism. Specifically, FhHDM-1 switched macrophages to a dependence on oxidative phosphorylation fuelled by fatty acids and supported by the induction of glutaminolysis. These changes mediated a decrease in glycolytic flux which consequently reduced pro-inflammatory cytokine production. This regulation of macrophage metabolism was maintained in vivo and furthermore, led to the reduction of histone methylation in bone marrow derived macrophages. This discovery suggests that FhHDM-1 can uniquely regulate the trained immune response; a phenotype of immune memory that underpins human immune-mediated diseases. Thus, this PhD project has unveiled a new paradigm of innate immune regulation, that explains the therapeutic efficacy of FhHDM-1.	en_US.UTF-8
dc.format	Thesis (PhD)
dc.language.iso	en_US	en_US.UTF-8
dc.relation	https://opus.lib.uts.edu.au/bitstream/10453/177148/1/thesis.pdf
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	The author owns the copyright in this thesis including all reproduction and reuse rights for the work. The work may not be altered without the permission of the copyright owner. Attribution is essential when quoting or paraphrasing from this thesis.
dc.rights	© 2023 Susel Mayra Loli Quinteros
dc.rights	au.edu.uts.lib/cph
dc.title	Modulation of macrophage metabolism and function by the helminth peptide FhHDM-1	en_US.UTF-8
dc.type	Thesis
utslib.copyright.status	open_access	*

Abstract:

Parasitic worms have evolved sophisticated strategies to regulate their host’s immune response, to prevent expulsion and establish chronic infections. Understanding how they achieve this offers a therapeutic strategy for the treatment of human diseases which are caused by unregulated inflammation. Previous characterisation of the liver fluke’s secreted proteins identified a peptide (termed FhHDM-1) that inhibited progression of immune-mediated disease in murine models of diabetes, multiple sclerosis and asthma. The aim of this PhD project was to uncover the mechanisms by which FhHDM-1 was mediating this beneficial effect. The research discovered that FhHDM-1 peptide regulates inflammation by reprogramming macrophage metabolism. Specifically, FhHDM-1 switched macrophages to a dependence on oxidative phosphorylation fuelled by fatty acids and supported by the induction of glutaminolysis. These changes mediated a decrease in glycolytic flux which consequently reduced pro-inflammatory cytokine production. This regulation of macrophage metabolism was maintained in vivo and furthermore, led to the reduction of histone methylation in bone marrow derived macrophages. This discovery suggests that FhHDM-1 can uniquely regulate the trained immune response; a phenotype of immune memory that underpins human immune-mediated diseases. Thus, this PhD project has unveiled a new paradigm of innate immune regulation, that explains the therapeutic efficacy of FhHDM-1.

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http://hdl.handle.net/10453/177148