An iron-mimicking, Trojan horse-entering fungi--has the time come for molecular imaging of fungal infections?

Abstract

Despite recent advancements in the diagnosis and management of fungal infections [1], invasive fungal diseases remain a major cause of morbidity and mortality in immunocompromised patients and are major drivers of elevated healthcare costs [2]. In this context, early diagnosis is a key factor. However, current diagnostic approaches, including laboratory tests and computer tomography, have limitations, especially in terms of sensitivity and specificity [3]. Therefore, empirical therapy has often evolved as the standard of care, irrespective of the immediate and long-term consequences in terms of cost, development of drug resistance, or toxicity [4]. An exceptional challenge is the development of imaging modalities providing not only high specificity and sensitivity but also localization of the infection site. In particular, nuclear medicine imaging techniques using radiolabelled probes (radiotracers) have the potential to specifically target the underlying pathophysiological mechanisms of the pathogen leading to molecular localization of the infection site in patients. Traditionally applied in the context of planar scintigraphy and single photon emission tomography (SPECT) in the past decade, Positron-Emission Tomography (PET) has evolved as a major clinical imaging technique, particularly in oncology [5]. This technology provides improved sensitivity and resolution based on the coincidence detection of photons emitted from radionuclei resulting from annihilation of positrons. Its tremendous success in oncology is mainly based on 2-[18F] fluorodeoxyglucose specifically accumulating in cells in dependence of their glucose consumption [6]. In this process, termed “molecular trapping,” the radiolabelled glucose molecule is actively transported into the cell, followed by its phosphorylation. The incorporated Fluor blocks further metabolic processing and traps the radionuclide 18F inside the cell, leading to an intense radioactive signal in affected cells. Other clinically used PET probes, such as [18F]-3′-fluoro-3′-deoxy-L-thymidine, [18F]-choline derivatives, or radiolabelled peptides, such as 68Ga-DOTATOC, show a similar trapping mechanism based on initial active transport in, or receptor-specific recognition by, diseased cells with promising clinical applications in oncology [7]. Besides accumulation in the target, favorable pharmacokinetics of radiotracers, such as rapid transport to and low retention in non-target sites/cells as well as efficient elimination from the body, ideally via renal excretion, are required. These features allow early imaging with short-lived radionuclides such as 18F with a half-life of 110 minutes, resulting in a low radiation burden for the patient. Therefore, a radiotracer for specific imaging of fungal infections should ideally fulfill similar criteria: specific accumulation in the pathogen combined with favorable pharmacokinetics, including rapid elimination from healthy tissue. Ideally, the pathogen should recognize the radiotracer as an apparent molecule of interest, boosting its active uptake and accumulation.