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1.
Nat Commun ; 10(1): 2297, 2019 05 24.
Article in English | MEDLINE | ID: mdl-31127085

ABSTRACT

Candida albicans is a fungal pathobiont, able to cause epithelial cell damage and immune activation. These functions have been attributed to its secreted toxin, candidalysin, though the molecular mechanisms are poorly understood. Here, we identify epidermal growth factor receptor (EGFR) as a critical component of candidalysin-triggered immune responses. We find that both C. albicans and candidalysin activate human epithelial EGFR receptors and candidalysin-deficient fungal mutants poorly induce EGFR phosphorylation during murine oropharyngeal candidiasis. Furthermore, inhibition of EGFR impairs candidalysin-triggered MAPK signalling and release of neutrophil activating chemokines in vitro, and diminishes neutrophil recruitment, causing significant mortality in an EGFR-inhibited zebrafish swimbladder model of infection. Investigation into the mechanism of EGFR activation revealed the requirement of matrix metalloproteinases (MMPs), EGFR ligands and calcium. We thus identify a PAMP-independent mechanism of immune stimulation and highlight candidalysin and EGFR signalling components as potential targets for prophylactic and therapeutic intervention of mucosal candidiasis.


Subject(s)
Candida albicans/immunology , Fungal Proteins/immunology , Host-Pathogen Interactions/immunology , Air Sacs/microbiology , Animals , Candida albicans/genetics , Candida albicans/metabolism , Candidiasis/immunology , Candidiasis/microbiology , Cell Line, Tumor , Disease Models, Animal , Epithelial Cells/immunology , Epithelial Cells/metabolism , Epithelial Cells/microbiology , ErbB Receptors/genetics , ErbB Receptors/immunology , ErbB Receptors/metabolism , Female , Fungal Proteins/genetics , Fungal Proteins/metabolism , Humans , MAP Kinase Signaling System/immunology , Matrix Metalloproteinases/immunology , Matrix Metalloproteinases/metabolism , Mice , Mice, Inbred BALB C , Mucous Membrane/immunology , Mucous Membrane/microbiology , Pharyngitis/immunology , Pharyngitis/microbiology , Phosphorylation , Zebrafish
2.
Pigment Cell Melanoma Res ; 22(5): 623-34, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19493315

ABSTRACT

Melanocortin-1 receptor (MC1R) and its ligands, alpha-melanocyte stimulating hormone (alphaMSH) and agouti signaling protein (ASIP), regulate switching between eumelanin and pheomelanin synthesis in melanocytes. Here we investigated biological effects and signaling pathways of ASIP. Melan-a non agouti (a/a) mouse melanocytes produce mainly eumelanin, but ASIP combined with phenylthiourea and extra cysteine could induce over 200-fold increases in the pheomelanin to eumelanin ratio, and a tan-yellow color in pelletted cells. Moreover, ASIP-treated cells showed reduced proliferation and a melanoblast-like appearance, seen also in melanocyte lines from yellow (A(y)/a and Mc1r(e)/ Mc1r(e)) mice. However ASIP-YY, a C-terminal fragment of ASIP, induced neither biological nor pigmentary changes. As, like ASIP, ASIP-YY inhibited the cAMP rise induced by alphaMSH analog NDP-MSH, and reduced cAMP level without added MSH, the morphological changes and depigmentation seemed independent of cAMP signaling. Melanocytes genetically null for ASIP mediators attractin or mahogunin (Atrn(mg-3J/mg-3J) or Mgrn1(md-nc/md-nc)) also responded to both ASIP and ASIP-YY in cAMP level, while only ASIP altered their proliferation and (in part) shape. Thus, ASIP-MC1R signaling includes a cAMP-independent pathway through attractin and mahogunin, while the known cAMP-dependent component requires neither attractin nor mahogunin.


Subject(s)
Agouti Signaling Protein/metabolism , Cyclic AMP/metabolism , Melanins/biosynthesis , Melanocytes/physiology , Membrane Proteins/metabolism , Signal Transduction/physiology , Ubiquitin-Protein Ligases/metabolism , Agouti Signaling Protein/genetics , Animals , Cell Proliferation , Cell Shape , Cells, Cultured , Hair Color/physiology , Melanins/metabolism , Melanocytes/cytology , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Pigmentation/physiology , Receptor, Melanocortin, Type 1/genetics , Receptor, Melanocortin, Type 1/metabolism , Ubiquitin-Protein Ligases/genetics
3.
Virol J ; 3: 15, 2006 Mar 22.
Article in English | MEDLINE | ID: mdl-16553948

ABSTRACT

BACKGROUND: The Coccolithoviridae is a recently discovered family of viruses that infect the marine coccolithophorid Emiliania huxleyi. Following on from the sequencing of the type strain EhV-86, we have sequenced a second strain, EhV-163. RESULTS: We have sequenced approximately 80% of the EhV-163 genome, equating to more than 200 full length CDSs. Conserved and variable CDSs and a gene replacement have been identified in the EhV-86 and EhV-163 genomes. CONCLUSION: The sequencing of EhV-163 has provided a wealth of information which will aid the re-annotating of the EhV-86 genome and identified a gene insertion in EhV-163.


Subject(s)
Genome, Viral , Phycodnaviridae/genetics , Base Sequence , Conserved Sequence , Genes, Viral/genetics , Genomics , Phycodnaviridae/classification , Sequence Analysis, DNA , Sequence Homology, Nucleic Acid
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