ZFIN ID: ZDB-PUB-160511-3
Calcineurin Orchestrates Lateral Transfer of Aspergillus fumigatus During Macrophage Cell Death
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.
Date: 2016
Source: American Journal of Respiratory and Critical Care Medicine   194(9): 1127-1139 (Journal)
Registered Authors: Mostowy, Serge
Keywords: Pulmonary Fungal Diseases; Macrophage; Necrosis; Aspergillus; Calcineurin
MeSH Terms:
  • Aspergillus fumigatus/metabolism*
  • Calcineurin/physiology*
  • Cell Death/physiology*
  • Humans
  • MAP Kinase Signaling System/physiology
  • Macrophages/microbiology*
  • Macrophages/pathology
  • Macrophages/physiology
  • Necrosis
  • Phagocytosis/physiology
  • Pulmonary Aspergillosis/immunology
  • Pulmonary Aspergillosis/physiopathology*
  • Reactive Oxygen Species/metabolism
  • Spores, Fungal/physiology
PubMed: 27163634 Full text @ Am. J. Respir. Crit. Care Med.
Pulmonary aspergillosis is a lethal mould infection in the immunocompromised host. Understanding initial control of infection, and how this is altered in the immunocompromised host, is a key goal for understanding the pathogenesis of pulmonary aspergillosis.
To characterise the outcome of human macrophage infection with Aspergillus fumigatus, and how this is altered in transplant recipients on calcineurin inhibitor immunosuppressants.
We defined the outcome of human macrophage infection with Aspergillus fumigatus, and the impact of calcineurin inhibitors, through a combination of single cell fluorescence imaging, transcriptomics, proteomics, and in vivo studies.
Macrophage phagocytosis of Aspergillus 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 Aspergillus 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 (VASP) envelope. Its relevance to the control of fungal germination was also shown by direct visualisation 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 hyphal escape.
These observations identify programmed necrosis-dependent lateral transfer of Aspergillus 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.