Siderophores: a potential role as a diagnostic for invasive fungal disease

Abstract

Purpose of reviewInvasive fungal diseases (IFDs) such as invasive aspergillosis continue to be associated with high morbidity and mortality while presenting significant diagnostic challenges. Siderophores are high-affinity Fe 3þ chelators produced by Aspergillus spp. and other fungi capable of causing IFD. Previously evaluated as a treatment target in mucormycosis, siderophores have recently emerged as new diagnostic targets for invasive aspergillosis and scedosporiosis. Here, we review the diagnostic potential of siderophores for diagnosing IFD, with a particular focus on invasive aspergillosis. Recent findingsThe major secreted siderophore of A. fumigatus, triacetylfusarinine C (TAFC), has been successfully detected by mass spectrometry in serum, BALF and urine of patients with invasive aspergillosis, with promising sensitivities and specificities in single-centre studies. Intracellular uptake of siderophores has also been utilized for imaging, wherein fungal siderophores have been conjugated with the easy-to-produce radioactive isotope gallium-68 ( 68 Ga) to visualize infected body sites in PET. For the Scedosporium apiospermum complex, another siderophore N(a)-methyl coprogen B has been shown promising as a marker for airway colonization in early studies. SummarySiderophores and particular TAFC have the potential to revolutionize diagnostic pathways for invasive aspergillosis and other mould infections. However, larger multicentre studies are needed to confirm these promising performances. Methods that allow rapid and cost-effective measurements in routine clinical practice need to be developed, particularly when TAFC is used as a biomarker in patient specimens.

Diagnosis of Aspergillosis in Horses

“…Gtx is an immunosuppressive fungal toxin that is secreted to the extracellular environment in response to fungal stress [ 40 ]. Studies have shown the utility of siderophores and/or gliotoxin in human blood and urine as useful biomarkers of Aspergillus infection, and we have detailed this recently [ 36 , 41 , 42 , 43 ].…”

InvasiveScedosporiumandLomentospora prolificansInfections in Australia: A Multicenter Retrospective Cohort Study

“…Expedited collection of blood cultures/tissue specimens, adoption of molecular techniques [ 13 ], and multisystem imaging are essential to timely identify disseminated infections. Siderophores may also have an emerging role as an early diagnostic biomarker in IFD [ 27 ], which merits future investigations.…”

Siderophore-Based Noninvasive Differentiation of Aspergillus fumigatus Colonization and Invasion in Pulmonary Aspergillosis

“…The fungal growth-dependent production of siderophores that mammalian hosts do not synthesize could enable the differentiation of colonization and invasion (infection) by A. fumigatus in critically ill patients. Our central hypothesis is that the transition to A. fumigatus invasion is accompanied by the appearance of fungal siderophores, as a response to an increased need for iron, in body fluids as a result of molecular leakage ( 12 ) ( Fig. 4 ).…”

“…The distinct roles of intracellular ferricrocin (Fc), hydroxyferricrocin (Hfc), extracellular fusarinine C (FsC), and triacetylfusarinine C (TafC) siderophores during A. fumigatus infection maintain iron homeostasis, conidial and hyphal iron storage, hyphal iron trafficking, reproductive and developmental processes, and oxidative stress resistance ( 6 , 8 , 10 , 11 ). Moreover, siderophores have been shown to serve as specific biomarkers of microbial infections ( 12 ). Additionally, A. fumigatus produces mycotoxins, including (among others) immunosuppressive gliotoxin (Gtx) ( 13 ), fumagillin, and fumitremorgin A ( 14 , 15 ).…”

“…We present clear links between germination or infection phase-dependent siderophore production and observations in critically ill patients. The active secretion of pathogen’s virulence factors ( 9 ) into the blood is a putative marker of the proliferation and angioinvasion of Aspergillus ( 12 ). This is the first report of the presence of TafB and Gtx in human urine samples and their potential value, together with TafC, for monitoring A. fumigatus invasion and the early, accurate diagnosis of IPA.…”