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Chapter 41 : A Perspective on Aspergillus fumigatus Research for the Next Ten Years
Category: Clinical Microbiology; Fungi and Fungal Pathogenesis
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In patients, invasive aspergillosis remains one of the most difficult diagnoses, and treatment is often late and unsuccessful. This chapter presents some thoughts and unpublished data from laboratories as well as questions that have been repeatedly discussed in meetings which should open new research avenues and may question some ongoing ones. Why is Aspergillus fumigatus pathogenic to human beings? This question automatically leads to the hypothesis of the presence of virulence factors specifically synthesized by A. fumigatus that are essential for invasion of its mammalian host. According to anti-aspergillus therapies, there are currently 11 antifungals with anti-Aspergillus activity, and several others are under evaluation in early clinical and preclinical studies. One of the most debated topics is the issue of combination antifungal therapy against invasive aspergillosis. The number of severely immunocompromised patients will continue to increase over the next 10 years as the field of medicine develops the technology to treat an increasing number of underlying conditions, such as malignancy and failed organs. Similarly, other medical disciplines such as rheumatology and gastroenterology are increasingly starting to use immunosuppressive agents for their recalcitrant patients, further multiplying the number of patients at risk for invasive aspergillosis.
Germination of conidia of A. fumigatus in vitro and in vivo. (A) Binding to and internalization of a conidium by an alveolar macrophage. (B) The first stages of germination (swelling) are not affected in the phagolysosome of the alveolar macrophage. (C) Killing of the conidium in an alveolar macrophage of an immunocompetent mouse. (D) Germination of the conidium in an alveolar macrophage of a cortisone acetate-treated mouse. (E) Three characteristic stages of conidial germination: a resting conidium with a thick melanin outer layer; a swollen conidium characterized by plasticization of the existing cell wall layers and synthesis of a new inner layer; and germling formation with disruption of the outer melanin layer and establishment of a polarized cell surrounded by the neosynthesized cell wall emerging through the outer conidia glucan layer. Adapted from Philippe et al. (2003) .
Percentage of killing of conidia of A. fumigatus (gray bars) and A. niger (black bars) by alveolar macrophages of immunocompetent (IC) and immunosuppressed (IS) mice recovered from bronchoal-veolar lavage fluid 24 h after conidia inhalation.
A. fumigatus strain virulence seen as differential fitness during joint infections. (A) Survival curve of cortisone acetate-treated mice infected intranasally with a unique strain, one of three strains with pigmentless conidia (W1 [ ], W2 [ ], W3 [ ]) or one of three strains with green-pigmented conidia (G1 [♦], G2 [▴], G3 [ ]; solid line, control). (B) Number of strains isolated from lungs of mice infected with the six strains together (hatched bars, intranasally; solid bars, intravenously). Note that strains G1 and G3 are the ones found in larger amounts (the most fit for growth in the lung) and that strain W3 is more pathogenic than the two other white strains and green strain G2. Adapted from Sarfati et al. (2002).
Two diagrams showing the interconnection between partners and disciplines in the study of aspergillosis in laboratory (A) and hospital (B) settings.