title: In silico modeling of spore inhalation reveals fungal persistence following low dose exposure.
abstract: The human lung is constantly exposed to spores of the environmental mould Aspergillus fumigatus, a major opportunistic pathogen. The spectrum of resultant disease is the outcome of complex host-pathogen interactions, an integrated, quantitative understanding of which lies beyond the ethical and technical reach permitted by animal studies. Here we construct a mathematical model of spore inhalation and clearance by concerted actions of macrophages and neutrophils, and use it to derive a mechanistic understanding of pathogen clearance by the healthy, immunocompetent host. In particular, we investigated the impact of inoculum size upon outcomes of single-dose fungal exposure by simulated titrations of inoculation dose, from 10(6) to 10(2) spores. Simulated low-dose (10(2)) spore exposure, an everyday occurrence for humans, revealed a counter-intuitive prediction of fungal persistence (>3 days). The model predictions were reflected in the short-term dynamics of experimental murine exposure to fungal spores, thereby highlighting the potential of mathematical modelling for studying relevant behaviours in experimental models of fungal disease. Our model suggests that infectious outcomes can be highly dependent upon short-term dynamics of fungal exposure, which may govern occurrence of cyclic or persistent subclinical fungal colonisation of the lung following low dose spore inhalation in non-neutropenic hosts.
authors.affiliation: Department of Bioengineering, Imperial College London, London, UK, SW7 2AZ.
authors.forename: Reiko J
authors.initials: RJ
authors.lastname: Tanaka
authors.affiliation: Department of Bioengineering, Imperial College London, London, UK, SW7 2AZ.
authors.forename: Neville J
authors.initials: NJ
authors.lastname: Boon
authors.affiliation: Department of Human Anatomy and Genetics, University of Oxford.
authors.forename: Katarina
authors.initials: K
authors.lastname: Vrcelj
authors.affiliation: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK.
authors.forename: Anita
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK, SW7 2AZ.
authors.forename: Carmelina
authors.initials: C
authors.lastname: Vinci
authors.affiliation: National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK, SW7 2AZ.
authors.forename: Darius
authors.initials: D
authors.lastname: Armstrong-James
authors.affiliation: Institute of Inflammation and Repair, Core Technology Facility, University of Manchester, UK, M13 9NT.
authors.forename: Elaine
authors.initials: E
authors.lastname: Bignell
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000378:metabolism / Q000473:pathology; D001232:Aspergillus fumigatus / Q000254:growth & development / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D006801:Humans; D016867:Immunocompromised Host; D019570:Inhalation Exposure; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008962:Models, Theoretical; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D013172:Spores, Fungal / Q000472:pathogenicity*
chemical_list: D016207:Cytokines