PUBLICATION

Macrophages protect Talaromyces marneffei conidia from myeloperoxidase-dependent neutrophil fungicidal activity during infection establishment in vivo

Authors
Ellett, F., Pazhakh, V., Pase, L., Benard, E.L., Weerasinghe, H., Azabdaftari, D., Alasmari, S., Andrianopoulos, A., Lieschke, G.J.
ID
ZDB-PUB-180609-25
Date
2018
Source
PLoS pathogens   14: e1007063 (Journal)
Registered Authors
Alasmari, Sultan, Benard, Erica L., Ellett, Felix, Lieschke, Graham J., Pase, Luke, Pazhakh, Vahid
Keywords
none
MeSH Terms
  • Animals
  • Aspergillus fumigatus/pathogenicity*
  • Immunity, Innate/immunology*
  • Spores, Fungal/immunology*
  • Mice
  • Peroxidase/metabolism
  • Talaromyces/pathogenicity*
  • Neutrophils/immunology*
  • Neutrophils/microbiology
  • Zebrafish/growth & development
  • Zebrafish/immunology*
  • Zebrafish/microbiology
  • Leukocytes/immunology
  • Leukocytes/microbiology
  • Macrophages/immunology*
  • Macrophages/microbiology
  • Phagocytosis
(all 17)
PubMed
29883484 Full text @ PLoS Pathog.
Abstract
Neutrophils and macrophages provide the first line of cellular defence against pathogens once physical barriers are breached, but can play very different roles for each specific pathogen. This is particularly so for fungal pathogens, which can occupy several niches in the host. We developed an infection model of talaromycosis in zebrafish embryos with the thermally-dimorphic intracellular fungal pathogen Talaromyces marneffei and used it to define different roles of neutrophils and macrophages in infection establishment. This system models opportunistic human infection prevalent in HIV-infected patients, as zebrafish embryos have intact innate immunity but, like HIV-infected talaromycosis patients, lack a functional adaptive immune system. Importantly, this new talaromycosis model permits thermal shifts not possible in mammalian models, which we show does not significantly impact on leukocyte migration, phagocytosis and function in an established Aspergillus fumigatus model. Furthermore, the optical transparency of zebrafish embryos facilitates imaging of leukocyte/pathogen interactions in vivo. Following parenteral inoculation, T. marneffei conidia were phagocytosed by both neutrophils and macrophages. Within these different leukocytes, intracellular fungal form varied, indicating that triggers in the intracellular milieu can override thermal morphological determinants. As in human talaromycosis, conidia were predominantly phagocytosed by macrophages rather than neutrophils. Macrophages provided an intracellular niche that supported yeast morphology. Despite their minor role in T. marneffei conidial phagocytosis, neutrophil numbers increased during infection from a protective CSF3-dependent granulopoietic response. By perturbing the relative abundance of neutrophils and macrophages during conidial inoculation, we demonstrate that the macrophage intracellular niche favours infection establishment by protecting conidia from a myeloperoxidase-dependent neutrophil fungicidal activity. These studies provide a new in vivo model of talaromycosis with several advantages over previous models. Our findings demonstrate that limiting T. marneffei's opportunity for macrophage parasitism and thereby enhancing this pathogen's exposure to effective neutrophil fungicidal mechanisms may represent a novel host-directed therapeutic opportunity.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
c264TgTransgenic Insertion
    gl8
      Point Mutation
      gl23TgTransgenic Insertion
        gl25TgTransgenic Insertion
          gl26TgTransgenic Insertion
            gl27TgTransgenic Insertion
              gl28TgTransgenic Insertion
                i113TgTransgenic Insertion
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                  Human Disease / Model
                  1 - 1 of 1
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                  Sequence Targeting Reagents
                  Target Reagent Reagent Type
                  csf3rMO3-csf3rMRPHLNO
                  csf3rMO5-csf3rMRPHLNO
                  il6rMO1-il6rMRPHLNO
                  il6stMO1-il6stMRPHLNO
                  irf8MO2-irf8MRPHLNO
                  spi1bMO1-spi1bMRPHLNO
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                  Fish
                  Antibodies
                  No data available
                  Orthology
                  No data available
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  EGFPEFGEGFP
                  GAL4FFEFGGAL4FF
                  GFPEFGGFP
                  KALTA4EFGKALTA4
                  mCherryEFGmCherry
                  NTREFGNTR
                  1 - 6 of 6
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                  Mapping
                  No data available