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Early and Non-invasive Diagnosis of Aspergillosis Revealed by Infection Kinetics Monitored in a Rat Model.

ABSTRACT: Background: Aspergillus fumigatus is a ubiquitous saprophytic airborne fungus responsible for more than one million deaths every year. The siderophores of A. fumigatus represent important virulence factors that contribute to the microbiome-metabolome dialog in a host. From a diagnostic point of view, the monitoring of Aspergillus secondary metabolites in urine of a host is promising due to the non-invasiveness, rapidity, sensitivity, and potential for standardization. Methods: Using a model of experimental aspergillosis in immunocompromised Lewis rats, the fungal siderophores ferricrocin (FC) and triacetylfusarinine C (TAFC) were monitored in rat urine before and after lung inoculation with A. fumigatus conidia. Molecular biomarkers in high-dose (HD) and low-dose (LD) infection models were separated using high performance liquid chromatography (HPLC) and were detected by mass spectrometry (MS). In the current work, we corroborated the in vivo MS infection kinetics data with micro-positron emission tomography/computed tomography (?PET/CT) kinetics utilizing 68Ga-labeled TAFC. Results: In the HD model, the initial FC signal reflecting aspergillosis appeared as early as 4 h post-infection. The results from seven biological replicates showed exponentially increasing metabolite profiles over time. In A. fumigatus, TAFC was found to be a less produced biomarker that exhibited a kinetic profile identical to that of FC. The amount of siderophores contributed by the inoculating conidia was negligible and undetectable in the HD and LD models, respectively. In the ?PET/CT scans, the first detectable signal in HD model was recorded 48 h post-infection. Regarding the MS assay, among nine biological replicates in the LD model, three animals did not develop any infection, while one animal experienced an exponential increase of metabolites and died on day 6 post-infection. All remaining animals had constant or random FC levels and exhibited few or no symptoms to the experiment termination. In the LD model, the TAFC concentration was not statistically significant, while the ?PET/CT scan was positive as early as 6 days post-infection. Conclusion: Siderophore detection in rat urine by MS represents an early and non-invasive tool for diagnosing aspergillosis caused by A. fumigatus. ?PET/CT imaging further determines the infection location in vivo and allows the visualization of the infection progression over time.

SUBMITTER: Skriba A

PROVIDER: S-EPMC6186828 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Early and Non-invasive Diagnosis of Aspergillosis Revealed by Infection Kinetics Monitored in a Rat Model.

Skriba Anton A Pluhacek Tomas T Palyzova Andrea A Novy Zbynek Z Lemr Karel K Hajduch Marian M Petrik Milos M Havlicek Vladimir V

Frontiers in microbiology 20181008

Background: Aspergillus fumigatus is a ubiquitous saprophytic airborne fungus responsible for more than one million deaths every year. The siderophores of A. fumigatus represent important virulence factors that contribute to the microbiome-metabolome dialog in a host. From a diagnostic point of view, the monitoring of Aspergillus secondary metabolites in urine of a host is promising due to the non-invasiveness, rapidity, sensitivity, and potential for standardization. ...[more]

PMID: 30349512

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Project description:With increasing frequency, clinical and laboratory-based mycologists are consulted on invasive fungal diseases caused by rare fungal species. This review aims to give an overview of the management of invasive aspergillosis (IA) caused by non-fumigatus Aspergillus spp.-namely A. flavus, A. terreus, A. niger and A. nidulans-including diagnostic and therapeutic differences and similarities to A. fumigatus. A. flavus is the second most common Aspergillus spp. isolated in patients with IA and the predominant species in subtropical regions. Treatment is complicated by its intrinsic resistance against amphotericin B (AmB) and high minimum inhibitory concentrations (MIC) for voriconazole. A. nidulans has been frequently isolated in patients with long-term immunosuppression, mostly in patients with primary immunodeficiencies such as chronic granulomatous disease. It has been reported to disseminate more often than other Aspergillus spp. Innate resistance against AmB has been suggested but not yet proven, while MICs seem to be elevated. A. niger is more frequently reported in less severe infections such as otomycosis. Triazoles exhibit varying MICs and are therefore not strictly recommended as first-line treatment for IA caused by A. niger, while patient outcome seems to be more favorable when compared to IA due to other Aspergillus species. A. terreus-related infections have been reported increasingly as the cause of acute and chronic aspergillosis. A recent prospective international multicenter surveillance study showed Spain, Austria, and Israel to be the countries with the highest density of A. terreus species complex isolates collected. This species complex seems to cause dissemination more often and is intrinsically resistant to AmB. Non-fumigatus aspergillosis is difficult to manage due to complex patient histories, varying infection sites and potential intrinsic resistances to antifungals. Future investigational efforts should aim at amplifying the knowledge on specific diagnostic measures and their on-site availability, as well as defining optimal treatment strategies and outcomes of non-fumigatus aspergillosis.

Dataset Information

Early and Non-invasive Diagnosis of Aspergillosis Revealed by Infection Kinetics Monitored in a Rat Model.

Publications

Early and Non-invasive Diagnosis of Aspergillosis Revealed by Infection Kinetics Monitored in a Rat Model.

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