Pathogenesis of Aspergillus fumigatus and the kinetics of galactomannan in an in vitro model of early invasive pulmonary aspergillosis: Implications for antifungal therapy

William W. Hope, Michael J. Kruhlak, Caron A. Lyman, Ruta Petraitiene, Vidmantas Petraitis, Andrea Francesconi, Miki Kasai, Diana Mickiene, Tin Sein, Joanne Peter, Amy M. Kelaher, Johanna E. Hughes, Margaret P. Cotton, Catherine J. Cotten, John Bacher, Sanjay Tripathi, Louis Bermudez, Timothy K. Maugel, Patricia M. Zerfas, John R. WingardGeorge L. Drusano, Thomas J. Walsh

Research output: Contribution to journalArticlepeer-review

Abstract

Background. Little is known about the pathogenesis of invasive pulmonary aspergillosis and the relationship between the kinetics of diagnostic markers and the outcome of antifungal therapy. Methods. An in vitro model of the human alveolus, consisting of a bilayer of human alveolar epithelial and endothelial cells, was developed. An Aspergillus fumigatus strain expressing green fluorescent protein was used. Invasion of the cell bilayer was studied using confocal and electron microscopy. The kinetics of culture, polymerase chain reaction, and galactomannan were determined. Galactomannan was used to measure the antifungal effect of macrophages and amphotericin B. A mathematical model was developed, and results were bridged to humans. Results. A. fumigatus penetrated the cellular bilayer 14-16 h after inoculation. Galactomannan levels were inextricably tied to fungal invasion and were a robust measure of the antifungal effect of macrophages and amphotericin B. Neither amphotericin nor macrophages alone was able to suppress the growth of A. fumigatus; rather, the combination was required. Monte Carlo simulations showed that human dosages of amphotericin B of at least 0.6 mg/kg were required to achieve adequate drug exposure. Conclusions. This model provides a strategy by which relationships among pathogenesis, immunological effectors, and antifungal drug therapy for invasive pulmonary aspergillosis may be further understood.

Original languageEnglish (US)
Pages (from-to)455-466
Number of pages12
JournalJournal of Infectious Diseases
Volume195
Issue number3
DOIs
StatePublished - Feb 1 2007

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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