Novel Clinical Diagnostic Targets For Detection of Invasive Mold Aspergillosis

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DESCRIPTION (provided by applicant): Invasive aspergillosis (IA) is a serious cause of mortality in immunocompromised patients, particularly those suffering from cancer, diabetes and HIV/AIDS or undergoing solid-organ or hematopoietic stem cell transplant (Ascioglu et al., 2002; Cornely, 2008). The occurrence of IA heightened over the past couple of decades because the number of patients with underlying risk factors continues to increase. Noteworthy, Aspergillus sp. account for approximately 15% of total fungal infections with a mortality that exceeds 80-90% in high risk groups (Walsh et al., 2008). Early treatment when the fungal burden is relatively low could be critical for the outcome of IMI. Immediate and conclusive detection of IA remains a conundrum since clinical symptoms are ambiguous and insufficient reliable diagnostic tools are available. Therefore, new diagnostic methods represent an unmet and pressing healthcare need. Fungal biomarkers have the potential to contribute to IA diagnosis and treatment monitoring as well as provide targets for antifungal therapy delivery to the site of infection. We have already published studies describing the Biopanning and Rapid Analysis of Selective Interacting Ligands (BRASIL) method and its utility in identification of peptides binding to Aspergillus hyphae and conidia (Giordano et al., 2001; Lionakis et al., 2005). More recently, we have expanded phage display- based targeting to nanotechnology applications through the direct-assembly of gold (Au) nanoparticles onto phage, exploiting the nanodimensions of the phage particle as a molecular network (Souza et al., 2006a). We generated stable and biologically active networks of direct-assembled Au-phage networks with concomitant unique and tunable chemical and physical properties. This tuning capability combined with the programmed targeting of the phage affords the integration of multiple functionalities into a single nanoassembly. We envision that either targeted Au-phage networks or labeled corresponding targeted peptides will become a reliable image platform for IA diagnosis and treatment monitoring. Our proposal is framed around the use of targeting phage Au nanoparticle molecular networks or labeled targeted peptides to diagnose iA. Our long-term goal is to develop a highly sensitive imaging diagnostic methodology for IA and other invasive fungal infections. To that end, will develop an imaging platform for diagnosis of IA, validate this platform in an animal model of invasive aspergillosis and enumerate its pharmacokinetical properties and toxicity to guide pre-clinical studies. PUBLIC HEALTH RELEVANCE: Invasive aspergillosis is a common cause of morbidity and mortality in immunosuppressed patients with leukemia and transplant recipients. Early diagnosis is of critical importance in improving the poor outcome of aspergillosis. Here we propose to use phage as targeting moieties for Gold (Au) nanoparticles based imaging for fungal infection diagnosis.