Sniffing out the hypoxia volatile metabolic signature ofAspergillus fumigatus

Abstract

Invasive Aspergillosis (IA) is a life-threatening infectious disease caused by fungi from the genus Aspergillus, with an associated mortality as high as 90% in certain populations. IA-associated pulmonary lesions are characteristically depleted in oxygen relative to normal lung tissue, and it has been shown that the most common causal agent of IA, Aspergillus fumigatus, must respond to low-oxygen environments for pathogenesis and disease progression. Previous studies have demonstrated marked alterations to the Aspergillus fumigatus transcriptome in response to low oxygen environments that induce a “hypoxia response.” Consequently, we hypothesized that these transcriptomic changes would alter the volatile metabolome and generate a volatile hypoxia signature. In the present study, we analyzed the volatile molecules produced by A. fumigatus in both oxygen replete (normoxia) and depleted (hypoxia) environments via headspace solid-phase microextraction coupled to two-dimensional gas chromatography-time-of-flight mass spectrometry (HS-SPME-GC×GC-TOFMS). Using the machine learning algorithm Random Forest, we identified 19 volatile molecules that were discriminatory between the four growth conditions assessed in this study (i.e., early hypoxia (1 h), late hypoxia (8 h), early normoxia (1 h), and late normoxia (8 h)), as well as a set of 19 that were discriminatory between late hypoxia cultures and all other growth conditions in aggregate. Nine molecules were common to both comparisons, while the remaining 20 were specific to only one of two. We assigned putative identifications to 13 molecules, of which six were most highly abundant in late hypoxia cultures. Previously acquired transcriptomic data identified putative biochemical pathways induced in hypoxia conditions that plausibly account for the production of a subset of these molecules, including 2,3-butanedione and 3-hydroxy-2-butanone. These two molecules may represent a novel hypoxia fitness pathway in A. fumigatus, and could be useful in the detection of hypoxia-associated A. fumigatus lesions that develop in established IA infections.

Aspergillus fumigatus tryptophan metabolic route differently affects host immunity

“…More similarly to the ΔidoA/B/C mutant, the ΔidoA/B mutant induced higher polymorphonuclear neutrophil recruitment and lung pathology ( Figures S6 E–S6G). We obtained similar results in p47 phox−/− mice that recapitulate chronic granulomatous disease ( Figures S7 A–S7C) and develop notable lung hypoxia resulting in a predisposition to Aspergill osis infection ( Rees et al., 2017 ; Shepardson et al., 2014 ). Here, these mice were highly susceptible to the ΔidoA/B/C mutant strain compared with the WT Aspergillus strain.…”

Aspergillus fumigatus and Aspergillosis in 2019

“…A. fumigatus also produces a multiplicity of volatile organic compounds, which are predominantly terpenes (146). However, the impact(s) of fungal VOCs on bacteria needs further study, especially since the volatome of A. fumigatus varies under different environmental situations (587). These studies show the very complex positive and negative interactions that can occur between a single bacterial inhabitant of the lung and A. fumigatus.…”

Characterization of hafting adhesives using comprehensive two‐dimensional gas chromatography coupled to time‐of‐flight mass spectrometry

“…It is usually recommended to not only rely on solely LRI for identification when individual standards are not injected under the exact same conditions. The documentation of these LRI values on a cyanopropyl‐based mid‐polar column is valuable due to the increasing number of VOC studies employing this column type for non‐targeted analyses .…”