Deciphering metabolic traits of the fungal pathogen Aspergillus fumigatus: redundancy vs. essentiality

Abstract

Incidence rates of infections caused by environmental opportunistic fungi have risen over recent decades. Aspergillus species have emerged as serious threat for the immunecompromised, and detailed knowledge about virulence-determining traits is crucial for drug target identification. As a prime saprobe, A. fumigatus has evolved to efficiently adapt to various stresses and to sustain nutritional supply by osmotrophy, which is characterized by extracellular substrate digestion followed by efficient uptake of breakdown products that are then fed into the fungal primary metabolism. These intrinsic metabolic features are believed to be related with its virulence ability. The plethora of genes that encode underlying effectors has hampered their in-depth analysis with respect to pathogenesis. Recent developments in Aspergillus molecular biology allow conditional gene expression or comprehensive targeting of gene families to cope with redundancy. Furthermore, identification of essential genes that are intrinsically connected to virulence opens accurate perspectives for novel targets in antifungal therapy.

Mutant characterization andin vivoconditional repression identify aromatic amino acid biosynthesis to be essential forAspergillus fumigatusvirulence

“…Fungal-specific genes and their products are prime candidates for interfering with pathogenesis, and metabolism represents a fundamental aspect of fungal physiology that is expedient to interfere with. However, recent studies on the physiology of A. fumigatus have revealed a high degree of versatility as well as redundancy with respect to nutrient utilization, 22 arising from the osmotrophic lifestyle of this prime saprobe, which hampers identification of distinct factors supporting in vivo growth. Unique enzymes of primary metabolism that may even be absent in the mammalian host have to be considered as highly promising candidates.…”

Regulation of Sulphur Assimilation Is Essential for Virulence and Affects Iron Homeostasis of the Human-Pathogenic Mould Aspergillus fumigatus

“…In recent years more and more evidence has been provided that fungal metabolism is a critical component of fungal virulence [65]. Accordingly, it has been proposed that based on this knowledge novel antifungal targets might be identified [10].…”

“…In opportunistic fungi like A. fumigatus , which does not seem to express host-specific virulence factors [8], [9], nutrient uptake and metabolic versatility have to be considered as non-specific virulence determinants (for a recent review see [10]) that, however, might represent promising antifungal targets [11]. To date, several metabolic routes fundamental for IPA manifestation have been identified: de novo UMP biosynthesis [12], the folate synthesis route [13], siderophore-mediated iron assimilation [14], or the methylcitrate cycle [15] are essential metabolic processes supporting in vivo growth and virulence of A. fumigatus [16].…”

Exploration of Sulfur Assimilation of Aspergillus fumigatus Reveals Biosynthesis of Sulfur-Containing Amino Acids as a Virulence Determinant

“…As a consequence, many research efforts are now directed toward the host-pathogen interplay to develop novel immunotherapies against infection. However, in recent years, it has also become clear that nutrient uptake and metabolic versatility are important, although nonspecific, virulence determinants of pathogenicity (2). Consequently, to fully understand A. fumigatus virulence, it is necessary to further decipher the metabolic status of the fungus during intrapulmonary growth.…”

“…The acquisition of nutrients by the invading microorganism is a requirement for its proliferation at the intimate host-pathogen interface. Despite their nonspecific character, efficient and versatile metabolic pathways have to be considered virulence determinants (2). The infected host organism, in turn, might restrict the access of pathogens to certain trace elements and metabolites in order to subvert their growth and invasion, a strategy that was recently called "nutritional immunity" (3).…”