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Jarocki V.M.,Ithree Institute | Santos J.,Ithree Institute | Santos J.,University of Technology, Sydney | Tacchi J.L.,Ithree Institute | And 7 more authors.
Open Biology | Year: 2015

Aminopeptidases are part of the arsenal of virulence factors produced by bacterial pathogens that inactivate host immune peptides. Mycoplasma hyopneumoniae is a genome-reduced pathogen of swine that lacks the genetic repertoire to synthesize amino acids and relies on the host for availability of amino acids for growth. M. hyopneumoniae recruits plasmin(ogen) onto its cell surface via the P97 and P102 adhesins and the glutamyl aminopeptidase MHJ-0125. Plasmin plays an important role in regulating the inflammatory response in the lungs of pigs infected with M. hyopneumoniae. We show that recombinant MHJ-0461 (rMHJ-0461) functions as a leucine aminopeptidase (LAP) with broad substrate specificity for leucine, alanine, phenylalanine, methionine and arginine and that MHJ-0461 resides on the surface of M. hyopneumoniae. rMHJ-0461 also binds heparin, plasminogen and foreign DNA. Plasminogen bound to rMHJ-0461 was readily converted to plasmin in the presence of tPA. Computational modelling identified putative DNA and heparin-binding motifs on solvent-exposed sites around a large pore on the LAP hexamer. We conclude that MHJ-0461 is a LAP that moonlights as a multifunctional adhesin on the cell surface of M. hyopneumoniae. © 2015 The Authors. Published.

Robinson M.W.,Ithree Institute | Robinson M.W.,Queen's University of Belfast | Alvarado R.,Ithree Institute | To J.,Ithree Institute | And 8 more authors.
FASEB Journal | Year: 2012

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.

Goodswen S.J.,Ithree Institute | Kennedy P.J.,Intelligent Systems Technology, Inc. | Ellis J.T.,Ithree Institute
Bioinformatics | Year: 2014

Summary: We present Vacceed, a highly configurable and scalable framework designed to automate the process of high-throughput in silico vaccine candidate discovery for eukaryotic pathogens. Given thousands of protein sequences from the target pathogen as input, the main output is a ranked list of protein candidates determined by a set of machine learning algorithms. Vacceed has the potential to save time and money by reducing the number of false candidates allocated for laboratory validation. Vacceed, if required, can also predict protein sequences from the pathogen's genome. © The Author 2014.

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