Abstract
Invasive pulmonary aspergillosis (IPA) caused by Aspergillus fumigatus is a life-threatening lung disease of immunocompromised patients. Diagnosis currently relies on non-specific chest CT, culture of the fungus from invasive lung biopsy, and detection of the cell wall carbohydrate galactomannan (GM) in serum or in BAL fluids recovered during invasive bronchoscopy. Urine provides an ideal bodily fluid for the non-invasive detection of pathogen biomarkers, with current urine-based immunodiagnostics for IPA focused on GM. Surrogate protein biomarkers might serve to improve disease detection. Here, we report the development of a monoclonal antibody (mAb), PD7, which is specific to A. fumigatus and related species in the section Fumigati, and which binds to its 18 kDa ribotoxin Asp f I. Using PD7, we show that the protein is secreted during hyphal development, and so represents an ideal candidate for detecting invasive growth. We have developed a lateral-flow device (Afu-LFD®) incorporating the mAb which has a limit of detection of ~15 ng Asp f I/mL urine. Preliminary evidence of the test’s diagnostic potential is demonstrated with urine from a patient with acute lymphoid leukaemia with probable IPA. The Afu-LFD® therefore provides a potential novel opportunity for non-invasive urine-based detection of IPA caused by A. fumigatus.
Highlights
Introduction nal affiliationsAspergillus fumigatus is the most important opportunistic mould pathogen of humans, causing a number of different respiratory diseases including aspergilloma, allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA), and invasive pulmonary aspergillosis (IPA), a lethal lung disease of mainly immunocompromised individuals, especially those with prolonged neutropenia, haematological malignancies, and bone marrow and solid organ transplants [1,2]
We report the development of a murine immunoglobulin class G1 (IgG1) monoclonal antibody (mAb), PD7®, raised against the A. fumigatus ribotoxin mitogillin, and which binds to an epitope conserved amongst the Aspergillus ribotoxins mitogillin, Asp f I, restrictocin, and α-sarcin
Using the mAb, which is specific to A. fumigatus and clinically-relevant sibling species in the section Fumigati [40,41,42], we have developed a lateral-flow assay known as Afu-LFD®
Summary
Introduction nal affiliationsAspergillus fumigatus is the most important opportunistic mould pathogen of humans, causing a number of different respiratory diseases including aspergilloma, allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA), and invasive pulmonary aspergillosis (IPA), a lethal lung disease of mainly immunocompromised individuals, especially those with prolonged neutropenia, haematological malignancies, and bone marrow and solid organ transplants [1,2]. Mycological evidence is reliant on slow and insensitive culture of the pathogen from invasive lung biopsy, or detection of biomarkers in serum [10], and/or in bronchoalveolar lavage fluids (BALf) recovered during invasive bronchoscopy [11]. While molecular imaging using antibody-guided positron emission tomography (immunoPET) holds enormous promise for the specific and non-invasive detection of Aspergillus lung infections in vivo [12,13,14], the technology is in its infancy and relies on sophisticated and expensive technology available in a limited number of hospitals only. There is a pressing need for the development of diagnostic tests that allow the detection of A. fumigatus biomarkers which are signatures of active infection, which are present in bodily fluids other than serum and invasive BALf, and which are readily accessible in critically ill patients
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