Desferrioxamine B-Mediated Pre-Clinical In Vivo Imaging of Infection by the Mold Fungus Aspergillus fumigatus.

Matthias Misslinger,Hubertus Haas,Joachim Pfister,Isabella Hubmann,Clemens Decristoforo,Katerina Bendova,Milos Petrik

doi:10.3390/jof7090734

Abstract

Fungal infections are a serious threat, especially for immunocompromised patients. Early and reliable diagnosis is crucial to treat such infections. The bacterially produced siderophore desferrioxamine B (DFO-B) is utilized by a variety of microorganisms for iron acquisition, while mammalian cells lack the uptake of DFO-B chelates. DFO-B is clinically approved for a variety of long-term chelation therapies. Recently, DFO-B-complexed gallium-68 ([68Ga]Ga-DFO-B) was shown to enable molecular imaging of bacterial infections by positron emission tomography (PET). Here, we demonstrate that [68Ga]Ga-DFO-B can also be used for the preclinical molecular imaging of pulmonary infection caused by the fungal pathogen Aspergillus fumigatus in a rat aspergillosis model. Moreover, by combining in vitro uptake studies and the chemical modification of DFO-B, we show that the cellular transport efficacy of ferrioxamine-type siderophores is impacted by the charge of the molecule and, consequently, the environmental pH. The chemical derivatization has potential implications for its diagnostic use and characterizes transport features of ferrioxamine-type siderophores.

Highlights

Invasive fungal infections, such as aspergillosis, bear a high risk for fatal outcomes
We aimed to evaluate (i) [68Ga]Ga-desferrioxamine B (DFO-B) for the in vivo imaging of aspergillosis in a rat infection model, (ii) the in vivo uptake of Ga-DFO-B versus Ga-DFO-E and (iii) the possibility of a pH-dependent charge affecting the uptake of DFO-B and modified DFO-B derivatives in comparison to the uncharged DFO-E
We demonstrated, for the first time, the successful application of [68Ga]Ga-DFO-B for imaging of A. fumigatus infections

Summary

Introduction

Invasive fungal infections, such as aspergillosis, bear a high risk for fatal outcomes. The gold standard for the diagnosis of fungal infections, such as invasive aspergillosis, is to culture the fungus from biological samples. This technique comes with advantageous yield of the specific pathogen, which allows testing for susceptibility to drugs used for treatment [3]. Cultures from the blood samples of invasive aspergillosis patients are usually negative [4] Biomarkers, such as galactomannan, (1–>3)-beta-D-glucan and DNA, are often not detected in blood samples in the early stages of invasive Aspergillus infections. For the early detection of Aspergillus infections, tissue biopsy or bronchoalveolar lavage fluid is required. These procedures are laborious, time-consuming and often lack sensitivity [5]. Time-saving diagnosis methods are required, as the speed fungal infection detection often determines the outcome of a fungal infection [6]

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