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Calcineurin Orchestrates Lateral Transfer of Aspergillus fumigatus during Macrophage Cell Death

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Title: Calcineurin Orchestrates Lateral Transfer of Aspergillus fumigatus during Macrophage Cell Death
Authors: Armstrong-James, DPH
Item Type: Journal Article
Abstract: Rationale: Pulmonary aspergillosis is a lethal mold infection in the immunocompromised host. Understanding initial control of infection and how this is altered in the immunocompromised host are key goals for comprehension of the pathogenesis of pulmonary aspergillosis. Objectives: To characterize the outcome of human macrophage infection with Aspergillus fumigatus and how this is altered in transplant recipients on calcineurin inhibitor immunosuppressants. Methods: We defined the outcome of human macrophage infection with A. fumigatus, as well as the impact of calcineurin inhibitors, through a combination of single-cell fluorescence imaging, transcriptomics, proteomics, and in vivo studies. Measurements and Main Results: Macrophage phagocytosis of A. fumigatus enabled control of 90% of fungal germination. However, fungal germination in the late phagosome led to macrophage necrosis. During programmed necroptosis, we observed frequent cell–cell transfer of A. fumigatus between macrophages, which assists subsequent control of germination in recipient macrophages. Lateral transfer occurred through actin-dependent exocytosis of the late endosome in a vasodilator-stimulated phosphoprotein envelope. Its relevance to the control of fungal germination was also shown by direct visualization in our zebrafish aspergillosis model in vivo. The calcineurin inhibitor FK506 (tacrolimus) reduced cell death and lateral transfer in vitro by 50%. This resulted in uncontrolled fungal germination in macrophages and also resulted in hyphal escape. Conclusions: These observations identify programmed, necrosis-dependent lateral transfer of A. fumigatus between macrophages as an important host strategy for controlling fungal germination. This process is critically dependent on calcineurin. Our studies provide fundamental insights into the pathogenesis of pulmonary aspergillosis in the immunocompromised host.
Issue Date: 10-May-2016
Date of Acceptance: 6-May-2016
URI: http://hdl.handle.net/10044/1/33585
DOI: 10.1164/rccm.201601-0070OC
ISSN: 1535-4970
Publisher: American Thoracic Society
Start Page: 1127
End Page: 1139
Journal / Book Title: American Journal of Respiratory and Critical Care Medicine
Volume: 194
Issue: 9
Copyright Statement: © 2016 by the American Thoracic Society
Sponsor/Funder: The Williams Trust Fund
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: N/A
G0902260
MR/K002708/1
MR/K000373/1
Keywords: Aspergillus
calcineurin
macrophage
necrosis
pulmonary fungal diseases
Pulmonary Fungal Diseases; Macrophage; Necrosis; Aspergillus; Calcineurin
Respiratory System
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:Department of Medicine (up to 2019)