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Clayton South, Australia

Gold M.J.,University of British Columbia | Antignano F.,University of British Columbia | Hughes M.R.,University of British Columbia | Zaph C.,University of British Columbia | And 3 more authors.
European Journal of Immunology | Year: 2016

In mouse models of infection with the gastrointestinal parasite Trichuris muris, appropriate dendritic-cell (DC) Ag sampling, migration, and presentation to T cells are necessary to mount a protective Th2-polarized adaptive immune response, which is needed to clear infection. SH2-containing inositol 5'-phosphatase 1 (SHIP-1) has been shown to be an important regulator of DC function in vitro through the negative regulation of the phosphoinositide 3-kinase (PI3K) pathway, but its role in vivo is relatively unexplored. In the current work, mice with a specific deletion of SHIP-1 in DCs (Ship1ΔDC) were infected with the parasite T. muris. Ship1ΔDC mice were susceptible to infection due to ineffective priming of Th2-polarized responses. This is likely due to an increased production of interleukin (IL) 12p40 by SHIP-1-deficient DCs, as in vivo antibody blockade of IL-12p40 was able to facilitate the clearing of infection in Ship1ΔDC mice. Our results describe a critical role for SHIP-1 in regulating the ability of DCs to efficiently prime Th2-type responses. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Heaton S.M.,Monash Biomedicine Discovery Institute | Heaton S.M.,Monash University | Borg N.A.,Monash Biomedicine Discovery Institute | Borg N.A.,Monash University | Dixit V.M.,Genentech
Journal of Experimental Medicine | Year: 2016

Viral infection activates danger signals that are transmitted via the retinoic acid-inducible gene 1-like receptor (RLR), nucleotide- binding oligomerization domain-like receptor (NLR), and Toll-like receptor (TLR) protein signaling cascades. This places host cells in an antiviral posture by up-regulating antiviral cytokines including type-I interferon (IFN-I). Ubiquitin modifications and cross-talk between proteins within these signaling cascades potentiate IFN-I expression, and inversely, a growing number of viruses are found to weaponize the ubiquitin modification system to suppress IFN-I. Here we review how host- and virus-directed ubiquitin modification of proteins in the RLR, NLR, and TLR antiviral signaling cascades modulate IFN-I expression. © 2016 Heaton et al. Source

Gorrell R.J.,Infection and Immunity Program | Gorrell R.J.,Monash Biomedicine Discovery Institute | Zwickel N.,Infection and Immunity Program | Zwickel N.,Monash Biomedicine Discovery Institute | And 6 more authors.
Journal of Infectious Diseases | Year: 2016

Previous studies suggest overrepresentation of particular polymorphisms within the Helicobacter pylori CagL hypervariable motif (CagLHM) in gastric cancer-associated isolates. However, these disease correlations were geographically variable and ambiguous. We compared the disease correlation of several hundred geographically diverse CagL sequences and identified 33 CagLHM sequence combinations with disparate geographical distribution, revealing substantial worldwide CagLHM diversity, particularly within Asian countries. Notably, polymorphisms E59 and I60 were significantly overrepresented, whereas D58 and E62 were underrepresented, in gastric cancer-associated H. pylori isolates worldwide. Thus, CagLHM regional diversity may contribute to the varied prevalence of H. pylori-related gastric cancer observed in diverse populations. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. Source

Sun Y.B.Y.,Monash Biomedicine Discovery Institute | Sun Y.B.Y.,Monash University | Qu X.,Monash Biomedicine Discovery Institute | Qu X.,Monash University | And 4 more authors.
Differentiation | Year: 2016

Renal fibrosis is a common characteristic of chronic kidney disease (CKD). Aberrant and excessive depositions of extracellular matrix (ECM) proteins in both glomeruli and interstitial regions are typical hallmarks of renal fibrosis and amplify the severity of kidney injury. To date, an approved therapy specifically targeted to renal fibrosis is needed to mitigate or even retard renal fibrosis. Recent findings have identified a unique population of myofibroblasts as a primary source of ECM in scar tissue formation. However, the origin of myofibroblasts in renal fibrosis remains the subject of controversial debates. The advancement in lineage tracing and immunofluorescent microscopy technologies have suggested that myofibroblasts may arise from a number of sources such as activated renal fibroblasts, pericytes, epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndoMT), bone marrow derived cells and fibrocytes. Recent studies also indicate that multiple ligands of TGF-β/Smads are the direct mediators for renal fibrosis. Consistently, inhibition of the TGF-β/Smads signaling pathway using various strategies significantly reduce renal fibrotic lesions and ameliorate kidney injury, suggesting that targeting the TGF-β/Smads signaling pathway could be a new strategy for effective therapies. In this review, we will briefly discuss the diverse origins of myofibroblasts and molecular pathways triggering renal fibrosis. Prospective therapeutic approaches based on those molecular mechanisms will hopefully offer exciting insights in the development of new therapeutic interventions for patients in the near future. © 2016. Source

Machuca M.A.,Monash Biomedicine Discovery Institute | Machuca M.A.,Monash University | Liu Y.C.,Monash Biomedicine Discovery Institute | Liu Y.C.,Monash University | And 6 more authors.
Journal of Structural Biology | Year: 2016

Chemotaxis and motility play an important role in the colonisation of avian and human hosts by Campylobacter jejuni. Chemotactic recognition of extracellular signals is mediated by the periplasmic sensing domain of methyl-accepting chemotactic proteins (membrane-embedded receptors). In this work, we report a high-resolution structure of the periplasmic sensing domain of transducer-like protein 1 (Tlp1), an aspartate receptor of C. jejuni. Crystallographic analysis revealed that it contains two Per-Arnt-Sim (PAS) subdomains. An acetate and chloride ions (both from the crystallisation buffer) were observed bound to the membrane-proximal and membrane-distal PAS subdomains, respectively. Surprisingly, despite being crystallised in the presence of aspartate, the structure did not show any electron density corresponding to this amino acid. Furthermore, no binding between the sensing domain of Tlp1 and aspartate was detected by microcalorimetric experiments. These structural and biophysical data suggest that Tlp1 does not sense aspartate directly; instead, ligand recognition is likely to occur indirectly via an as yet unidentified periplasmic binding protein. © 2016 Elsevier Inc. Source

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