Cited by 71Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Infections and Studies

Calcineurin Orchestrates Lateral Transfer of Aspergillus fumigatus during Macrophage Cell Death

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Shah, Anand, Kannambath, Shichina, Herbst, Susanne, Rogers, Andrew, Soresi, Simona, Carby, Martin, Reed, Anna, Mostowy, Serge +3 more·2016·American Journal of Respiratory and Critical Care Medicine

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.

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  • Ca2+-calcineurin signaling orchestrates a novel process of lateral transfer of germinating conidia between macrophages via an actin-dependent process.

    “Ca2+-calcineurin signaling also orchestrates a novel process of lateral transfer of germinating conidia between macrophages via an actin-dependent process (201).”

    From Aspergillus fumigatus and Aspergillosis in 2019 (2019) · cites this paper as [201]

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Authors
Shah, A., Kannambath, S., Herbst, S., Rogers, A., Soresi, S., Carby, M., Reed, A., Mostowy, S., Fisher, M. C., Shaunak, S., & Armstrong-James, D. P.
Affiliations
  • Imperial College London (GB)
  • Royal Brompton & Harefield NHS Foundation Trust (GB)
Corresponding author
Armstrong-James, Darius P.
Venue
American Journal of Respiratory and Critical Care Medicine
Published
2016-11-01
Volume
194
Issue
9
Pages
1127-1139
ISSN
  • 1073-449X (ISSN-L)
  • 1535-4970
OpenAlex
W2359912528
Cited by
71
References
48
Citations by year
2026: 2 · 2025: 8 · 2024: 6 · 2023: 4 · 2022: 10 · 2021: 5 · 2020: 7 · 2019: 9 · 2018: 9 · 2017: 11
FWCI
8.87
Type
journal article
Language
en
Open access
Locations
  • American Journal of Respiratory and Critical Care Medicine (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • St George's Online Research Archive (St George's University of London) (acceptedVersion)
  • LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
  • Spiral (Imperial College London) (submittedVersion)
Funders
  • Medical Research Council (G0902260/1, MR/K002708/1)
  • Wellcome Trust Research Career Development Fellowship (WT097411MA)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Keywords
Aspergillus fumigatus, pulmonary aspergillosis, calcineurin, FK506, tacrolimus, calcineurin inhibitors, lateral transfer, fungal spore germination, phagosome, late endosomes, VASP, immunosuppression, transplant recipients, zebrafish model
MeSH terms
Aspergillus fumigatus, Humans, Macrophages, Necrosis, Phagocytosis, Spores, Fungal, Cell Death, Reactive Oxygen Species, Calcineurin, MAP Kinase Signaling System, Pulmonary Aspergillosis

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