Aspergillus fumigatus The Versatile Saprophyte

A. fumigatus is a saprophytic fungus with a worldwide prevalence. It is one of the most common species of airborne spore-producing fungi in the world (Shelton et al., 2002). Its buoyant airborne spores (conidia), ability to utilize varied carbon sources and thermotolerance enable it to survive in areas with widely different climates and environments. Conidia of this fungus can be isolated nearly everywhere, from the winds of the Sahara to the snows of Antarctica (Braude, 1986). It sporulates profusely, with each conidiophore producing thousands of tiny (2-3 micron diameter), bluish-green hydrophobic conidia that are easily dispersed into the atmosphere. Environmental surveys indicate that in areas of human habitation, approximately 1-100 A. fumigatus conidia are typically found per cubic meter of air, and thus all humans inhale at least several hundred conidia per day (Latge, 1999).

The species exhibits little variation, either within geographic regions or on a global scale, suggesting that the population is in continual gene flow across continents (Pringle, 2005; Rydholm, 2006). A. fumigatus is abundant in moist soil rich in organic materials and feeds mainly upon decaying vegetation undergoing aerobic decomposition (Thom & Raper, 1945; Mullins, 1976). It is especially plentiful in man-made environments and in disturbed soils (Rydholm, 2006). The thermophylic ability of A. fumigatus to grow at temperatures of 55°C and

K. Kavanagh (ed.), New Insights in Medical Mycology. © Springer 2007

survive at up to 70°C enables it to successfully dominate the compost fungal microflora (Beffa et al., 1998; Ryckeboer et al., 2003).

Recent genomic analysis strongly suggest that A. fumigatus is primarily a herbivorous leaf eater: a survey of its genome has shown that it contains the full armamentarium of enzymes necessary to degrade plants, but lacks ligninases necessary to digest wood (Tekaia & Latge, 2005).

Although considered to lack a sexual life cycle, the presence of mating type and sex-related genes in its genome support the assertion that A. fumigatus exhibits the potential to reproduce by sexual means (Dyer & Paoletti, 2005; Paoletti et al., 2005). In contrast, the closely related Neosartorya fischeri (94% average protein identity with A. fumigatus) exhibits a functional sexual life cycle. Interestingly N. fischeri rarely infects humans despite its ubiquitous distribution, raising the possibility that a genomic comparison between it and A. fumigatus may identify specific virulence determinants in the latter (Wortman et al., 2006). Recent typing analysis of clinical A. fumigatus isolates has revealed that a substantial number were misidentified and are in fact closely related species. They include the potentially drug resistant Aspergillus lentulus and Aspergillus udagawae (Balajee et al., 2006).

A. fumigatus causes a spectrum of diseases depending on the immune status of the host: A. fumigatus is exceptional among microorganisms in being both an opportunistic pathogen and a major allergen, capable of causing a wide range of clinical manifestations depending on the immune status of the host (Denning, 1998; Casadevall & Pirofski, 2003; Denning et al., 2006). It causes damage primarily at the extremes of both weak and strong immune responses (Figure 8.1). In immunocompetent hypersensitive individuals, conidial inhalation can result in various allergic responses such as allergic bronchopulmonary aspergillosis (ABPA), extrinsic allergic alveolitis (EAA), allergic aspergillus sinusitis, and asthma with fungal sensitization (Moss, 2005; Denning et al., 2006) (Figure 8.1B). These reactions are defined as an immune hypersensitivity reaction to specific Aspergillus antigens, with tissue damage being mostly self-inflicted by infiltrating neutrophils and eosinophils (Tillie-Leblond & Tonnel, 2005). They can be effectively controlled during their early stages by administration of corticosteroids to temper the immune response and in the case of ABPA, antifungals such as itraconazole or voriconazole to inhibit fungal growth (TillieLeblond & Tonnel, 2005).

In immunocompetent persons, A. fumigatus infection may very rarely lead to chronic conditions such as aspergilloma or fungus ball of the lung and sinus. Hyphal growth is restricted to the aspergilloma, with no invasion of the surrounding tissue. Treatment ranges from observation without intervention to antifungal administration and surgical resection in extreme cases.

In immunocompromised patients, inhaled A. fumigatus conidia germinate and invade the sinus, airway, or lung tissues, causing acute or subacute invasive infection depending on the severity of neutropenia (Figure 8. 1C). In severely compromised patients (<200 neutrophils/mm3) hyphae invade and penetrate surrounding tissue and blood vessels, causing acute invasive aspergillosis (IA) a severe and generally fatal infection (30-90% mortality when treated) (Denning, 1998; Kontoyiannis & Bodey, 2002). Damage is caused primarily by the toxic

Figure 8.1 The outcome of A. fumigatus lung infection depends on the immune status of the host. (A) In the immunocompetent host, conidia are rapidly destroyed by alveolar macrophages and neutrophils. (B) In the hypersensitive host, conidia initiate an allergic response leading to self-inflicted tissue damage. (C) In the immunodeficient host conidia germinate, invading the lung tissue and blood vessels

Figure 8.1 The outcome of A. fumigatus lung infection depends on the immune status of the host. (A) In the immunocompetent host, conidia are rapidly destroyed by alveolar macrophages and neutrophils. (B) In the hypersensitive host, conidia initiate an allergic response leading to self-inflicted tissue damage. (C) In the immunodeficient host conidia germinate, invading the lung tissue and blood vessels soup of enzymes and secondary metabolites secreted by the fungus during its vigorous growth in the host organs. This growth occurs because the host lacks effective lines of defense, primarily composed of resident alveolar macrophages and recruited neutrophils. The high mortality rate following treatment can only partially be attributed to a lack of truly effective fungicidal drugs; additional factors complicating an effective cure are the weak general condition of the patients and the difficulty in diagnosing the disease (Kontoyiannis & Bodey,

2002). Because of the increase in the number of immunosuppressed patients following aggressive modern chemotherapy and immunosuppressive regimens, the incidence of IA has increased fourfold during the last 15 years (Steinbach & Stevens, 2003). Ten percent of all deaths in patients who undergo allogeneic bone marrow transplants are attributed to IA, which has a mortality rate of approximately 90% in that setting. IA is found at autopsy in about 20% (95/484) of patients with hematologic malignancies. Furthermore, the financial burden of IAassociated hospitalization is enormous: US data from 1996 estimated the total cost of IA treatment to be US $633 million, with an average cost per case of US $65,000 (Dasbach, 2000). Because of its importance, most research involving A. fumigatus virulence factors has centered on identifying those factors involved in IA, and they will be the primary focus of this review.

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