title: A helminth cathelicidin-like protein suppresses antigen processing and presentation in macrophages via inhibition of lysosomal vATPase.
abstract: We previously reported the identification of a novel family of immunomodulatory proteins, termed helminth defense molecules (HDMs), that are secreted by medically important trematode parasites. Since HDMs share biochemical, structural, and functional characteristics with mammalian cathelicidin-like host defense peptides (HDPs), we proposed that HDMs modulate the immune response via molecular mimicry of host molecules. In the present study, we report the mechanism by which HDMs influence the function of macrophages. We show that the HDM secreted by Fasciola hepatica (FhHDM-1) binds to macrophage plasma membrane lipid rafts via selective interaction with phospholipids and/or cholesterol before being internalized by endocytosis. Following internalization, FhHDM-1 is rapidly processed by lysosomal cathepsin L to release a short C-terminal peptide (containing a conserved amphipathic helix that is a key to HDM function), which then prevents the acidification of the endolysosomal compartments by inhibiting vacuolar ATPase activity. The resulting endolysosomal alkalization impedes macrophage antigen processing and prevents the transport of peptides to the cell surface in conjunction with MHC class II for presentation to CD4(+) T cells. Thus, we have elucidated a novel mechanism by which helminth pathogens alter innate immune cell function to assist their survival in the host.
authors.affiliation: Ithree Institute, University of Technology Sydney, Sydney, Australia. mark.robinson@qub.ac.uk
authors.forename: Mark W
authors.initials: MW
authors.lastname: Robinson
authors.forename: Raquel
authors.initials: R
authors.lastname: Alvarado
authors.forename: Joyce
authors.initials: J
authors.lastname: To
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hutchinson
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Dowdell
authors.forename: Maria
authors.initials: M
authors.lastname: Lund
authors.forename: Lynne
authors.initials: L
authors.lastname: Turnbull
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Whitchurch
authors.forename: Bronwyn A
authors.initials: BA
authors.lastname: O'Brien
authors.forename: John P
authors.initials: JP
authors.lastname: Dalton
authors.forename: Sheila
authors.initials: S
authors.lastname: Donnelly
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000145:classification* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000947:Antigens, Helminth / Q000378:metabolism*; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism; D005210:Fasciola hepatica / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D005802:Genes, MHC Class II; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism; D008969:Molecular Sequence Data; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000947:Antigens, Helminth; D015801:Helminth Proteins; D011994:Recombinant Proteins; D056668:Cathepsin L; D000251:Adenosine Triphosphatases