Towards Translational ImmunoPET/MR Imaging of Invasive Pulmonary Aspergillosis: The Humanised Monoclonal Antibody JF5 Detects <i>Aspergillus</i> Lung Infections <i>In Vivo</i>

Davies, Genna; Rolle, Anna-Maria; Maurer, Andreas; Spycher, Philipp R.; Schillinger, Claudia; Solouk-Saran, Djamschid; Hasenberg, Mike; Weski, Juliane; Fonslet, Jesper; DuBois, Adrien S.; Boschetti, Frédéric; Denat, Franck; Gunzer, Matthias; Eichner, Martin; Ryder, Lauren S.; Jensen, Mikael; Schibli, Roger; Pichler, Bernd J.; Wiehr, Stefan; Thornton, Christopher R.

doi:10.7150/thno.20919

Cited by 56 publications

(64 citation statements)

References 31 publications

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“…Advances in radiological technologies also deserve mention. Use of Aspergillus-specific tracers (e.g., siderophores and monoclonal antibodies) for immuno-PET detection is investigated, but such approaches for NAIMIs are still lacking (146)(147)(148). The immuno-PET approach shows promise as a theragnostic tool in mold infections (148).…”

Section: Advances In Diagnostic Strategiesmentioning

confidence: 99%

Therapeutic Challenges of Non- Aspergillus Invasive Mold Infections in Immunosuppressed Patients

Lamoth

Kontoyiannis

2019

Antimicrob Agents Chemother

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While Aspergillus spp. remain the major cause of invasive mold infections in hematologic cancer patients and transplant recipients, other opportunistic molds, such as Mucorales, Fusarium, and Scedosporium spp. are increasingly encountered in an expanding population of patients with severe and prolonged immunosuppression. High potential for tissue invasion and dissemination, resistance to multiple antifungals and high mortality rates are hallmarks of these non-Aspergillus invasive mold infections (NAIMIs). Assessment of drug efficacy is particularly difficult in the complex treatment scenarios of NAIMIs. Specifically, correlation between in vitro susceptibility and in vivo responses to antifungals is hard to assess, in view of the multiple, frequently interrelated factors influencing outcomes, such as pharmacokinetic/pharmacodynamic parameters determining drug availability at the site of infection, the net state of immune suppression, delay in diagnosis, or surgical debulking of infectious foci. Our current therapeutic approach of NAIMIs should evolve toward a better integration of the dynamic interactions between the pathogen, the drug and the host. Innovative concepts of experimental research may consist in manipulating the host immune system to induce a specific antifungal response or targeted drug delivery. In this review, we discuss the challenges in the management of NAIMIs and provide an update about the latest advances in diagnostic and therapeutic approaches.

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Section: Advances In Diagnostic Strategiesmentioning

confidence: 99%

Therapeutic Challenges of Non- Aspergillus Invasive Mold Infections in Immunosuppressed Patients

Lamoth

Kontoyiannis

2019

Antimicrob Agents Chemother

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“…Inhalation models have been already described since the early 90’s [58] and their value has been proven [59]. A model of intratracheal intubation with ventilation has also been described to trigger a better distribution of spores [12, 60]. Hence, we believe that such models should be better characterized to assess whether these should be adopted as the gold standard for pulmonary infection models.…”

Section: Discussionmentioning

confidence: 99%

3D light sheet fluorescence microscopy of lungs to dissect local host immune -Aspergillus fumigatusinteractions

Amich

Mokhtari

Strobel

et al. 2019

Preprint

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Rudolf-Virchow-Zentrum für Experimentelle Biomedizin. 35 Universität Würzburg. 36 Josef-Schneider-Straße 2, Haus D15. D -97080 Würzburg 37 38 39 40 41 42 43 44 45 VISUAL ABSTRACT 46 Quantitative light sheet fluorescence microscopy to dissect local host-pathogen interactions 47 ABSTRACT 51Aspergillus fumigatus is an opportunistic fungal pathogen that can cause life-threatening 52 invasive lung infections in immunodeficient patients. The cellular and molecular processes of 53 infection during onset, establishment and progression are highly complex and depend on 54 both fungal attributes and the immune status of the host. Therefore, preclinical animal 55 models are paramount to investigate and gain better insight into the infection process. Yet, 56 despite their extensive use, commonly employed murine models of invasive pulmonary 57 aspergillosis are not well understood due to analytical limitations. Here we present 58 quantitative light sheet fluorescence microscopy (LSFM) to describe fungal growth and the 59 local immune response in whole lungs at cellular resolution within its anatomical context. We 60 analyzed three very common murine models of pulmonary aspergillosis based on 61 immunosuppression with corticosteroids, chemotherapy-induced leukopenia or 62 myeloablative irradiation. LSFM uncovered distinct architectures of fungal growth and 63 degrees of tissue invasion in each model. Furthermore, LSFM revealed the spatial 64 distribution, interaction and activation of two key immune cell populations in antifungal 65 defense: alveolar macrophages and polymorphonuclear neutrophils. Interestingly, the 66 patterns of fungal growth correlated with the detected effects of the immunosuppressive 67 regimens on the local immune cell populations. Moreover, LSFM demonstrates that the 68 commonly used intranasal route of spore administration did not result in the desired intra-69 alveolar deposition, as more than 60% of fungal growth occurred outside of the alveolar 70 space. Hence, LSFM allows for more rigorous characterization of murine models of invasive 71 pulmonary aspergillosis and pinpointing their strengths and limitations. 72 IMPORTANCE 73The use of animal models of infection is essential to advance our understanding of complex 74 host-pathogen interactions that take place during Aspergillus fumigatus lung infections. As in 75 the case of humans, mice need to be immunosuppressed to become susceptible to invasive 76 pulmonary aspergillosis, the most serious infection caused by A. fumigatus. There are 77 several immunosuppressive regimens that are routinely used to investigate fungal growth 78 and/or immune responses in murine models of invasive pulmonary aspergillosis (IPA). 79However, the precise consequences that each immunosuppressive model has on the local 80 immune populations and for fungal growth are not completely understood. Here we 81 employed light sheet fluorescence microscopy (LSFM) to analyze whole lungs at cellular 82 resolution, to pin down the scenario commonly used IPA models. Our results will be ...

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“…Imaging with antibodies has, until very recently, been the domain of cancer detection ( Mestel, 2017 ), with limited application in infectious disease diagnostics ( Rolle and Wiehr, 2017 ). However, recent studies have demonstrated the enormous potential of antibody-guided PET/MRI (immunoPET/MRI) technologies to dramatically improve the molecular imaging of viral ( Santangelo et al, 2014 ), bacterial ( Wiehr et al, 2016 ), and fungal ( Rolle et al, 2016 ; Davies et al, 2017 ) infections in vivo , with the real possibility of precision medicine for infectious diseases in the near future ( Jain, 2017 ). ImmunoPET/MRI marries functionality of PET with the specificity of mAbs and anatomical depiction of MRI.…”

Section: Aspergillosis Imaging With Monoclonal Antibody Jf5mentioning

confidence: 99%

Molecular Imaging of Invasive Pulmonary Aspergillosis Using ImmunoPET/MRI: The Future Looks Bright

Thornton

2018

Front. Microbiol.

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Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of immuno-compromised humans caused by the ubiquitous environmental mold Aspergillus. Biomarker tests for the disease lack sensitivity and specificity, and culture of the fungus from invasive lung biopsy is slow, insensitive, and undesirable in critically ill patients. A computed tomogram (CT) of the chest offers a simple non-intrusive diagnostic procedure for rapid decision making, and so is used in many hematology units to drive antifungal treatment. However, radiological indicators that raise the suspicion of IPA are either transient signs in the early stages of the disease or not specific for Aspergillus infection, with other angio-invasive molds or bacterial pathogens producing comparable radiological manifestations in a chest CT. Improvements to the specificity of radiographic imaging of IPA have been attempted by coupling CT and positron emission tomography (PET) with [18F]fluorodeoxyglucose ([18F]FDG), a marker of metabolic activity well suited to cancer imaging, but with limited use in invasive fungal disease diagnostics due to its inability to differentiate between infectious etiologies, cancer, and inflammation. Bioluminescence imaging using single genetically modified strains of Aspergillus fumigatus has enabled in vivo monitoring of IPA in animal models of disease. For in vivo detection of Aspergillus lung infections in humans, radiolabeled Aspergillus-specific monoclonal antibodies, and iron siderophores, hold enormous potential for clinical diagnosis. This review examines the different experimental technologies used to image IPA, and recent advances in state-of-the-art molecular imaging of IPA using antibody-guided PET/magnetic resonance imaging (immunoPET/MRI).

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Towards Translational ImmunoPET/MR Imaging of Invasive Pulmonary Aspergillosis: The Humanised Monoclonal Antibody JF5 Detects Aspergillus Lung Infections In Vivo

Cited by 56 publications

References 31 publications

Therapeutic Challenges of Non- Aspergillus Invasive Mold Infections in Immunosuppressed Patients

Therapeutic Challenges of Non- Aspergillus Invasive Mold Infections in Immunosuppressed Patients

3D light sheet fluorescence microscopy of lungs to dissect local host immune -Aspergillus fumigatusinteractions

Molecular Imaging of Invasive Pulmonary Aspergillosis Using ImmunoPET/MRI: The Future Looks Bright

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