Aspergillus fumigatus metabolism: clues to mechanisms of in vivo fungal growth and virulence

Abstract

Aspergillus fumigatus is a saprophytic fungus commonly found in soil and compost piles. In immunocompromised patients it takes on a sinister form as a potentially lethal opportunistic human pathogen. We currently have a limited understanding of the in vivo growth mechanisms used by A. fumigatus during invasive pulmonary aspergillosis (IPA). The ability of A. fumigatus to adapt to various microenvironments encountered during growth in the human host may explain why A. fumigatus is the most frequently occurring opportunistic pathogenic mold. The transcriptional and metabolic responses to changing microenvironments found in the mammalian lung require the activation of pathways implicated in resistance to unique stresses. Thus, the production of primary metabolites in vivo may give clues to the critical pathways used by A. fumigatus to cause disease in human hosts. We recently have identified primary metabolites in the mammalian lung typically associated with fungal growth under hypoxic environments suggesting that A. fumigatus may encounter low oxygen tensions during IPA. These and other studies on A. fumigatus metabolism are the focus of this review.

Fig. 1

Scheme of different stresses A. fumigatus likely encounters within the lung. The cellular defense involving phagocytosis and killing is mediated by alveolar macrophages, polymorphonuclear cells (PMN) and monocytes. The non-cellular defense is mediated by antileukoprotease (ALP), tracheal antimicrobial peptide (TAP) and lysozyme. A. fumigatus interferes with the host defense by the release of superoxide dismutase (SOD), A. fumigatus diffusible product (AfD) and conidial inhibitory factor (conidial IF) from conidia, and by the release of complement inhibitory factor (complement IF), toxins, and proteases from hyphae [61]. The response of A. fumigatus to hypoxia includes the transcription of hypoxia related genes like srbA and likely the switch to various pathways of fermentation (e.g. alcohol and ammonia fermentation). The lack of nutrients at the site of infection can be compensated by activating the cross-pathway control system and degradation of proteins to acquire amino acids for protein biosynthesis and possibly the glyoxylate cycle to produce carbohydrates from fats that are available at the site of infection.

Fig 2

Histopathology of A. fumigatus infection in an experimental murine model of invasive pulmonary aspergillosis. Hematoxylin and eosin stain of control, uninfected mouse lung showing clear, open alveoli and no inflammation, and a section from a lung infected with A. fumigatus 3 days post-infection. Significant tissue necrosis, hyphal invasion, collapse of alveoli, and inflammation are evident (black arrows). Significant hypoxia is likely present at an infection site such as this, and the abundant tissue destruction likely liberates proteins and other nutrients that can be used by the fungus for in vivo growth.

Fig 3

A. fumigatus shows different responses to hypoxic conditions. 1 × 10⁶ conidia were spotted on glucose minimal medium (GMM) (2% glucose), ethanol minimal medium (EMM) (2% ethanol) and glycerol minimal medium (GlyMM) (2% glycerol) and incubated under normoxia (21% oxygen) or hypoxia (1% oxygen) at 37°C for 48 hours.