Universität zu Köln

Ellett, Felix ORCID: 0000-0003-4941-4346, Pazhakh, Vahid, Pase, Luke, Benard, Erica L., Weerasinghe, Harshini, Azabdaftari, Denis, Alasmari, Sultan, Andrianopoulos, Alex and Lieschke, Graham J. (2018). Macrophages protect Talaromyces marneffei conidia from myeloperoxidase-dependent neutrophil fungicidal activity during infection establishment in vivo. PLoS Pathog., 14 (6). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7374

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ellett, Felix UNSPECIFIED orcid.org/0000-0003-4941-4346 UNSPECIFIED Pazhakh, Vahid UNSPECIFIED UNSPECIFIED UNSPECIFIED Pase, Luke UNSPECIFIED UNSPECIFIED UNSPECIFIED Benard, Erica L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Weerasinghe, Harshini UNSPECIFIED UNSPECIFIED UNSPECIFIED Azabdaftari, Denis UNSPECIFIED UNSPECIFIED UNSPECIFIED Alasmari, Sultan UNSPECIFIED UNSPECIFIED UNSPECIFIED Andrianopoulos, Alex UNSPECIFIED UNSPECIFIED UNSPECIFIED Lieschke, Graham J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-183693
DOI:	10.1371/journal.ppat.1007063
Journal or Publication Title:	PLoS Pathog.
Volume:	14
Number:	6
Date:	2018
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1553-7374
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PENICILLIUM-MARNEFFEI; ASPERGILLUS-FUMIGATUS; CANDIDA-ALBICANS; ZEBRAFISH MODEL; HISTOPLASMA-CAPSULATUM; TRANSGENIC ZEBRAFISH; G-CSF; CELL; REVEALS; GROWTH Multiple languages Microbiology; Parasitology; Virology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18369