Modeling Approaches Reveal New Regulatory Networks in Aspergillus fumigatus Metabolism

Abstract

Systems biology approaches are extensively used to model and reverse-engineer gene regulatory networks from experimental data. Indoleamine 2,3-dioxygenases (IDOs)—belonging in the heme dioxygenase family—degrade l-tryptophan to kynurenines. These enzymes are also responsible for the de novo synthesis of nicotinamide adenine dinucleotide (NAD+). As such, they are expressed by a variety of species, including fungi. Interestingly, Aspergillus may degrade l-tryptophan not only via IDO but also via alternative pathways. Deciphering the molecular interactions regulating tryptophan metabolism is particularly critical for novel drug target discovery designed to control pathogen determinants in invasive infections. Using continuous time Bayesian networks over a time-course gene expression dataset, we inferred the global regulatory network controlling l-tryptophan metabolism. The method unravels a possible novel approach to target fungal virulence factors during infection. Furthermore, this study represents the first application of continuous-time Bayesian networks as a gene network reconstruction method in Aspergillus metabolism. The experiment showed that the applied computational approach may improve the understanding of metabolic networks over traditional pathways.

Aspergillus fumigatus tryptophan metabolic route differently affects host immunity

“…We recently proposed that mathematical modeling and reverse-engineered gene-regulatory networks from experimental data could be used to determine the interconnectivity of multiple metabolic fungal pathways ( Acerbi et al., 2020 ). Using continuous time Bayesian networks over a time-course gene expression dataset, we inferred the global regulatory network controlling Trp metabolism.…”

“…Using continuous time Bayesian networks over a time-course gene expression dataset, we inferred the global regulatory network controlling Trp metabolism. The model revealed that high Trp levels activate the Trp catabolic routes independently, whereas low levels may interconnect the different metabolic pathways Article ll OPEN ACCESS (Acerbi et al, 2020). Going forward, it is becoming evident that Aro pathway activation can disrupt lung tolerogenic responses.…”

A network-based model ofAspergillus fumigatuselucidates regulators of development and defensive natural products of an opportunistic pathogen

“…There exist at least seven studies in Aspergillus fumigatus that examined different sets of regulatory relationships involved in specific biological processes (9)(10)(11)(12)(13)(14)(15)(16). For instance, Guthke et al studied the regulatory mechanism(s) that allows A. fumigatus to adapt to a dramatic temperature shift during the infection process; in their study they used an inferred GRN to hypothesize that erg11, a gene necessary for ergosterol synthesis, modulates the expression of genes encoding heat shock proteins and the allergen RPL3 in response to a temperature shift of 30 °C to 48 °C (9).…”

“…mRNA transcriptomic profiles) to reverse engineer GRN structure, offer a popular and cost-effective technique to provide an initial view of the GRN that can be experimentally verified. For example, Acerbi et al applied a computational method using the transcriptome of several A. fumigatus genes to infer the regulatory connections involved in tryptophan synthesis (11). Although these studies have shed light on GRNs in A. fumigatus, the datasets have been limited to specific environmental conditions (e.g., tryptophan, temperature).…”