Aspergillus fumigatus is one of the most ubiquitous of the airborne saprophytic fungi. Humans and animals constantly inhale numerous conidia of this fungus. The conidia are normally eliminated in the immunocompetent host by innate immune mechanisms, and aspergilloma and allergic bronchopulmonary aspergillosis, uncommon clinical syndromes, are the only infections observed in such hosts. Thus, A. fumigatus was considered for years to be a weak pathogen. With increases in the number of immunosuppressed patients, however, there has been a dramatic increase in severe and usually fatal invasive aspergillosis, now the most common mold infection worldwide. In this review, the focus is on the biology of A. fumigatus and the diseases it causes. Included are discussions of (i) genomic and molecular characterization of the organism, (ii) clinical and laboratory methods available for the diagnosis of aspergillosis in immunocompetent and immunocompromised hosts, (iii) identification of host and fungal factors that play a role in the establishment of the fungus in vivo, and (iv) problems associated with antifungal therapy.

Aspergillus fumigatus and Aspergillosis

SUMMARY Aspergillus fumigatus is one of the most ubiquitous of the airborne saprophytic fungi. Humans and animals constantly inhale numerous conidia of this fungus. The conidia are normally eliminated in the immunocompetent host by innate immune mechanisms, and aspergilloma and allergic bronchopulmonary aspergillosis, uncommon clinical syndromes, are the only infections observed in such hosts. Thus, A. fumigatus was considered for years to be a weak pathogen. With increases in the number of immunosuppressed patients, however, there has been a dramatic increase in severe and usually fatal invasive aspergillosis, now the most common mold infection worldwide. In this review, the focus is on the biology of A. fumigatus and the diseases it causes. Included are discussions of (i) genomic and molecular characterization of the organism, (ii) clinical and laboratory methods available for the diagnosis of aspergillosis in immunocompetent and immunocompromised hosts, (iii) identification of host and fungal factors that play a role in the establishment of the fungus in vivo, and (iv) problems associated with antifungal therapy.

Aspergillus fumigatus and aspergillosis.

Aspergillus species are globally ubiquitous saprophytes found in a variety of ecological niches. Almost 200 species of aspergilli have been identified, less than 20 of which are known to cause human disease. Among them, Aspergillus fumigatus is the most prevalent and is largely responsible for the increased incidence of invasive aspergillosis (IA) in the immunocompromised patient population. IA is a devastating illness, with mortality rates in some patient groups reaching as high as 90%. Studies identifying and assessing the roles of specific factors of A. fumigatus that contribute to the pathogenesis of IA have traditionally focused on single-gene deletion and mutant characterization. In combination with recent large-scale approaches analyzing global fungal responses to distinct environmental or host conditions, these studies have identified many factors that contribute to the overall pathogenic potential of A. fumigatus. Here, we provide an overview of the significant findings regarding A. fumigatus pathogenesis as it pertains to invasive disease.

Pathogenesis of Aspergillus fumigatus in Invasive Aspergillosis

Various putative virulence factors of Aspergillus fumigatus have been studied over the past decades. A. fumigatus gliotoxin is a potent inhibitor of the mucociliary system. Several fungal metabolites interfere with phagocytosis and opsonization including toxins, 'conidial inhibitory factor', 'A. fumigatus diffusible product' and 'complement inhibitory factor'. A. fumigatus can bind specifically to different host tissues components, whereas toxins give a general and significant immunosuppressive effect on host defences. Circumstantial evidence links the production of elastinolytic proteases with the ability to cause disease. However, none of the reports demonstrates conclusively a decisive role for any of the virulence factors described thus far. It is conceivable that proteolytic enzyme activities such as those expressed by AFAlp are one of a number of factors, each with a minor effect, that combine to facilitate disease progression.

Putative virulence factors of Aspergillus fumigatus

Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 hypersensitivity lung disease in response to Aspergillus fumigatus that affects asthmatic and cystic fibrosis (CF) patients. Sensitization to A. fumigatus is common in both atopic asthmatic and CF patients, yet only 1-2% of asthmatic and 7–9% of CF patients develop ABPA. ABPA is characterized by wheezing and pulmonary infiltrates which may lead to pulmonary fibrosis and/or bronchiectasis. The inflammatory response is characterized by Th2 responses to Aspergillus allergens, increased serum IgE and eosinophilia. A number of genetic risks have recently been identified in the development of ABPA. These include HLA-DR and HLA-DQ, IL-4 receptor alpha chain (IL-4RA) polymorphisms, IL-10-1082GA promoter polymorphisms, surfactant protein A2 (SP-A2) polymorphisms, and cystic fibrosis transmembrane conductance regulator gene (CFTR) mutations. The studies indicate that ABPA patients are genetically at risk to develop skewed and heightened Th2 responses to A. fumigatus antigens. These genetic risk studies and their consequences of elevated biologic markers may aid in identifying asthmatic and CF patients who are at risk to the development of ABPA. Furthermore, these studies suggest that immune modulation with medications such as anti-IgE, anti-IL-4 and/or IL-13 monoclonal antibodies may be helpful in the treatment of ABPA.

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Allergic Bronchopulmonary Aspergillosis in Asthma and Cystic Fibrosis

BACKGROUND: Aspergillus fumigatus is an opportunistic pathogen to which asthmatic subjects are particularly susceptible. The ability of spores of A fumigatus to bind to pulmonary cells and basement membrane proteins was investigated to determine the mechanisms involved in this susceptibility. METHODS: Cells of the A549 pulmonary epithelial cell line or purified basement membrane proteins were immobilised on the wells of microtitre plates. They were then exposed to spores of A fumigatus in suspension, with or without various pretreatments of the spores, cells, and proteins. Adherent spores were counted by light microscopy. RESULTS: Spores of A fumigatus bound in a concentration dependent manner to A549 epithelial cells and pretreatment of cells with interferon gamma (2500 units/ml) caused a significant doubling of spore binding. Binding of spores to A549 cells was inhibited by about a third by pre-incubation of the spores with fibrinogen (100 micrograms/ml). Spores bound specifically to extracellular matrix (ECM) components laid down by A549 cells, and pretreatment of the ECM components with hydrogen peroxide (25-80 microM) enhanced spore binding by approximately one third. They also bound specifically and in a saturable manner to purified fibrinogen, fibronectin, laminin, type I collagen, and type IV collagen. Pre-incubation of spores with Arg-Gly-Asp tripeptide (RGD; 50-200 micrograms/ ml) inhibited binding to fibronectin and type I collagen by 50%. CONCLUSIONS: This study suggests that the presence of activated epithelial cells and the exposure of basement membrane that occurs in asthma, together with oxidant stress, may facilitate the colonisation of the asthmatic lung by A fumigatus. The RGD sequence may be involved in spore binding to some ECM proteins. Free fibrinogen may protect against binding of A fumigatus spores to the pulmonary epithelium.

https://thorax.bmj.com/content/thoraxjnl/51/12/1203.full.pdf

K. Donaldson

Papers

Binding of Aspergillus fumigatus spores to lung epithelial cells and basement membrane proteins: relevance to the asthmatic lung.