title: Calcineurin Orchestrates Lateral Transfer of Aspergillus fumigatus during Macrophage Cell Death.
abstract: 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.
  
  
  
  To characterize 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 A. fumigatus, as well as the impact of calcineurin inhibitors, through a combination of single-cell fluorescence imaging, transcriptomics, proteomics, and in vivo studies.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 1 National Heart and Lung Institute.
authors.forename: Anand
authors.initials: A
authors.lastname: Shah
authors.affiliation: 1 National Heart and Lung Institute.
authors.forename: Shichina
authors.initials: S
authors.lastname: Kannambath
authors.affiliation: 1 National Heart and Lung Institute.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herbst
authors.affiliation: 2 Histopathology Department and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rogers
authors.affiliation: 3 Lung Transplant Unit, Royal Brompton and Harefield Hospitals, Harefield, United Kingdom.
authors.forename: Simona
authors.initials: S
authors.lastname: Soresi
authors.affiliation: 3 Lung Transplant Unit, Royal Brompton and Harefield Hospitals, Harefield, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Carby
authors.affiliation: 3 Lung Transplant Unit, Royal Brompton and Harefield Hospitals, Harefield, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Reed
authors.affiliation: 4 Medical Research Council Centre for Molecular Bacteriology and Infection.
authors.forename: Serge
authors.initials: S
authors.lastname: Mostowy
authors.affiliation: 5 School of Public Health, and.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Fisher
authors.affiliation: 6 Department of Infectious Diseases and Immunity, Imperial College London, London, United Kingdom; and.
authors.forename: Sunil
authors.initials: S
authors.lastname: Shaunak
authors.affiliation: 1 National Heart and Lung Institute.
authors.forename: Darius P
authors.initials: DP
authors.lastname: Armstrong-James
mesh_terms: D001232:Aspergillus fumigatus / Q000378:metabolism*; D019703:Calcineurin / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008264:Macrophages / Q000382:microbiology* / Q000473:pathology / Q000502:physiology; D009336:Necrosis; D010587:Phagocytosis / Q000502:physiology; D055732:Pulmonary Aspergillosis / Q000276:immunology / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013172:Spores, Fungal / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species; D019703:Calcineurin
keywords: Aspergillus; calcineurin; macrophage; necrosis; pulmonary fungal diseases