title: A parasitic helminth-derived peptide that targets the macrophage lysosome is a novel therapeutic option for autoimmune disease.
abstract: Parasitic worms (helminths) reside in their mammalian hosts for many years. This is attributable, in part, to their ability to skew the host's immune system away from pro-inflammatory responses and towards anti-inflammatory or regulatory responses. This immune modulatory ability ensures helminth longevity within the host, while simultaneously minimises tissue destruction for the host. The molecules that the parasite releases clearly exert potent immune-modulatory actions, which could be exploited clinically, for example in the prophylactic and therapeutic treatment of pro-inflammatory and autoimmune diseases. We have identified a novel family of immune-modulatory proteins, termed helminth defence molecules (HDMs), which are secreted by several medically important helminth parasites. These HDMs share biochemical and structural characteristics with mammalian cathelicidin-like host defence peptides (HDPs), which are significant components of the innate immune system. Like their mammalian counterparts, parasite HDMs block the activation of macrophages via toll like receptor (TLR) 4 signalling, however HDMs are significantly less cytotoxic than HDPs. HDMs can traverse the cell membrane of macrophages and enter the endolysosomal system where they reduce the acidification of lysosomal compartments by inhibiting vacuolar (v)-ATPase activity. In doing this, HDMs can modulate critical cellular functions, such as cytokine secretion and antigen processing/presentation. Here, we review the role of macrophages, specifically their lysosomal mediated activities, in the initiation and perpetuation of pro-inflammatory immune responses. We also discuss the potential of helminth defence molecules (HDMs) as therapeutics to counteract the pro-inflammatory responses underlying autoimmune disease. Given the current lack of effective, non-cytotoxic treatment options to limit the progression of autoimmune pathologies, HDMs open novel treatment avenues.
authors.affiliation: School of Medical and Molecular Biosciences, University of Technology, Sydney, Sydney, NSW, Australia.
authors.forename: Raquel
authors.initials: R
authors.lastname: Alvarado
authors.affiliation: School of Medical and Molecular Biosciences, University of Technology, Sydney, Sydney, NSW, Australia.
authors.forename: Bronwyn
authors.initials: B
authors.lastname: O'Brien
authors.affiliation: School of Medical and Molecular Biosciences, University of Technology, Sydney, Sydney, NSW, Australia.
authors.forename: Akane
authors.initials: A
authors.lastname: Tanaka
authors.affiliation: School of Biological Sciences, Medical Biology Centre, Queen's University, Belfast, Belfast, Northern Ireland, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Dalton
authors.affiliation: School of Medical and Molecular Biosciences, University of Technology, Sydney, Sydney, NSW, Australia; The i3 Institute, University of Technology, Sydney, Sydney, NSW, Australia. Electronic address: Sheila.Donnelly@uts.edu.au.
authors.forename: Sheila
authors.initials: S
authors.lastname: Donnelly
mesh_terms: D000818:Animals; D000947:Antigens, Helminth / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000276:immunology; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000517:prevention & control; D006376:Helminths / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D056747:Immunomodulation / Q000187:drug effects; D007167:Immunotherapy; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D010455:Peptides / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D054804:Cathelicidins
chemical_list: D000947:Antigens, Helminth; D023181:Antimicrobial Cationic Peptides; D010455:Peptides; D054804:Cathelicidins
keywords: Autoimmune disease; Cathelicidin; Helminth; Lysosome; Macrophage; Toll like receptor