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Macrophages protect Talaromyces marneffei conidia from myeloperoxidase-dependent neutrophil fungicidal activity during infection establishment in vivo.
Ellett, Felix; Pazhakh, Vahid; Pase, Luke; Benard, Erica L; Weerasinghe, Harshini; Azabdaftari, Denis; Alasmari, Sultan; Andrianopoulos, Alex; Lieschke, Graham J.
Afiliação
  • Ellett F; Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
  • Pazhakh V; Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • Pase L; Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
  • Benard EL; Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
  • Weerasinghe H; Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
  • Azabdaftari D; Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • Alasmari S; Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • Andrianopoulos A; Genetics, Genomics and Systems Biology, School of BioSciences, University of Melbourne, Victoria, Australia.
  • Lieschke GJ; Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
PLoS Pathog ; 14(6): e1007063, 2018 06.
Article em En | MEDLINE | ID: mdl-29883484
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Aspergillus fumigatus / Esporos Fúngicos / Peixe-Zebra / Talaromyces / Imunidade Inata / Macrófagos / Neutrófilos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Aspergillus fumigatus / Esporos Fúngicos / Peixe-Zebra / Talaromyces / Imunidade Inata / Macrófagos / Neutrófilos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article