title: In vivo bioluminescence imaging and histopathopathologic analysis reveal distinct roles for resident and recruited immune effector cells in defense against invasive aspergillosis.
abstract: BACKGROUND
  Invasive aspergillosis (IA) is a major cause of infectious morbidity and mortality in immune compromised patients. Studies on the pathogenesis of IA have been limited by the difficulty to monitor disease progression in real-time. For real-time monitoring of the infection, we recently engineered a bioluminescent A. fumigatus strain.
  
  
  RESULTS
  In this study, we demonstrate that bioluminescence imaging can track the progression of IA at different anatomic locations in a murine model of disease that recapitulates the natural route of infection. To define the temporal and functional requirements of distinct innate immune cellular subsets in host defense against respiratory A. fumigatus infection, we examined the development and progression of IA using bioluminescence imaging and histopathologic analysis in mice with four different types of pharmacologic or numeric defects in innate immune function that target resident and recruited phagocyte subsets. While bioluminescence imaging can track the progression and location of invasive disease in vivo, signals can be attenuated by severe inflammation and associated tissue hypoxia. However, especially under non-inflammatory conditions, such as cyclophosphamide treatment, an increasing bioluminescence signal reflects the increasing biomass of alive fungal cells.
  
  
  CONCLUSIONS
  Imaging studies allowed an in vivo correlation between the onset, peak, and kinetics of hyphal tissue invasion from the lung under conditions of functional or numeric inactivation of phagocytes and sheds light on the germination speed of conidia under the different immunosuppression regimens. Conditions of high inflammation -either mediated by neutrophil influx under corticosteroid treatment or by monocytes recruited during antibody-mediated depletion of neutrophils- were associated with rapid conidial germination and caused an early rise in bioluminescence post-infection. In contrast, 80% alveolar macrophage depletion failed to trigger a bioluminescent signal, consistent with the notion that neutrophil recruitment is essential for early host defense, while alveolar macrophage depletion can be functionally compensated.
authors.affiliation: Unité de Recherche Cytokines & Inflammation, Institut Pasteur Paris France. oumaima.granet@pasteur.fr
authors.forename: Oumaïma
authors.initials: O
authors.lastname: Ibrahim-Granet
authors.forename: Grégory
authors.initials: G
authors.lastname: Jouvion
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Hohl
authors.forename: Sabrina
authors.initials: S
authors.lastname: Droin-Bergère
authors.forename: François
authors.initials: F
authors.lastname: Philippart
authors.forename: Oh Yoen
authors.initials: OY
authors.lastname: Kim
authors.forename: Minou
authors.initials: M
authors.lastname: Adib-Conquy
authors.forename: Reto
authors.initials: R
authors.lastname: Schwendener
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Cavaillon
authors.forename: Matthias
authors.initials: M
authors.lastname: Brock
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004002:Clodronic Acid / Q000494:pharmacology / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000494:pharmacology; D004271:DNA, Fungal / Q000737:chemistry; D004195:Disease Models, Animal; D018450:Disease Progression; D006651:Histocytochemistry; D007165:Immunosuppression Therapy; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008163:Luminescent Measurements / Q000379:methods; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000166:cytology / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D009000:Monocytes / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D030781:Organisms, Genetically Modified; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051598:Whole Body Imaging / Q000379:methods
chemical_list: D004271:DNA, Fungal; D008164:Luminescent Proteins; D004002:Clodronic Acid; D003520:Cyclophosphamide