William W Hope

Author address: 

The University of Manchester


The lung can be directly implicated in approximately 90% of cases of invasive pulmonary aspergillosis. The alveolar-capillary barrier separates the airspace (alveolus) from the pulmonary capillary, and consists of the alveolar epithelial cells (type I and II), the basement membrane and the pulmonary capillary endothelium. Resident pulmonary alveolar macrophages are a critical innate immunological defense mechanism. The initiation of invasive disease requires the evasion of innate host defenses and transgression of the alveolarcapillary barrier. Cell culture models demonstrate that alveolar epithelial cells freely endocytose conidia, where the majority are killed in lysosomes. A fraction may escape and undergo intracellular germination to form hyphae; thus, invasion of the alveolar capillary barrier may be initiated from an intracellular location. A variety of imaging techniques demonstrate that invading hyphae pursue a direct intracellular route. An in vitro model of the alveolar-capillary barrier and a well validated neutropenic rabbit model of invasive pulmonary aspergillosis demonstrate that hyphae penetrate into the endothelial compartment (the pulmonary capillary) approximately 14-16 hours post inoculation. These models demonstrate the intimate relationship between invasion and the kinetics of the clinically relevant biomarker, galactomannan. Models of early invasive pulmonary aspergillosis suggest: (1) many of the important pathological events occur within the initial 24 hours, well before any clinical manifestations of disease are likely to be apparent; (2) small delays in the administration of appropriate antifungal therapy may have profound effects on the antifungal effect; (3) pulmonary alveolar macrophages exhibit saturable killing; (4) both innate immunological effectors and antifungal agents are required for maximal antifungal effect; and (5) the intracellular location of hyphae may be important for immunological and pharmacological evasion. An improved understanding of the pathogenesis of early fungal invasion will lead to a range of diagnostic and therapeutic strategies which will serve as an important means of optimizing the outcome of immunocompromised patients with invasive pulmonary aspergillosis. References: 1. Hope WW, Kruhlak MJ, Lyman CA, Petraitiene R, Petraitis V, Francesconi A, Kasai M, Mickiene D, Sein T, Peter J, Kelaher AM, Hughes JE, Cotton MP, Cotten CJ, Bacher J, Tripathi S, Bermudez L, Maugel TK, Zerfas PM, Wingard JR, Drusano GL and Walsh TJ. Pathogenesis of Aspergillus fumigatus and the kinetics of galactomannan in an in vitro model of early invasive pulmonary aspergillosis: implications for antifungal therapy. J Infect Dis 2007;195:455-466 2. Filler SG, Sheppard DC. Fungal invasion of normally non-phagocytic host cells. PLoS Pathog 2006;2:e129 3. Wasylnka JA, Moore MM. Uptake of Aspergillus fumigatus Conidia by phagocytic and nonphagocytic cells in vitro: quantitation using strains expressing green fluorescent protein. Infect Immun 2002;70:3156-3163 4. Wasylnka JA, Moore MM. Aspergillus fumigatus conidia survive and germinate in acidic organelles of A549 epithelial cells. J Cell Sci 2003;116:1579-1587

abstract No: 


Full conference title: 

3rd Advances Against Aspergillosis
    • AAA 3rd (2008)