Damping excessive viral-induced IFN-γ rescues the impaired anti-Aspergillus host immune response in influenza-associated pulmonary aspergillosis.

Autor:	Seldeslachts L; Department of Imaging and Pathology, Biomedical MRI Unit/MoSAIC, KU Leuven, 3000, Leuven, Belgium., Staels F; Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunity, KU Leuven, 3000, Leuven, Belgium., Gkountzinopoulou M; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 71300, Heraklion, Crete, Greece; Department of Clinical Microbiology and Microbial Pathogenesis, School of Medicine, University of Crete, Greece., Jacobs C; Department of Microbiology, Immunology and Transplantation, Laboratory for Clinical Infectious and Inflammatory Disorders, KU Leuven, 3000, Leuven, Belgium., Tielemans B; Department of Imaging and Pathology, Biomedical MRI Unit/MoSAIC, KU Leuven, 3000, Leuven, Belgium., Vanhoffelen E; Department of Imaging and Pathology, Biomedical MRI Unit/MoSAIC, KU Leuven, 3000, Leuven, Belgium., Reséndiz-Sharpe A; Department of Imaging and Pathology, Biomedical MRI Unit/MoSAIC, KU Leuven, 3000, Leuven, Belgium., De Herdt L; Department of Imaging and Pathology, Biomedical MRI Unit/MoSAIC, KU Leuven, 3000, Leuven, Belgium., Haughton J; Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunity, KU Leuven, 3000, Leuven, Belgium., Prezzemolo T; Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunity, KU Leuven, 3000, Leuven, Belgium., Burton O; Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunity, KU Leuven, 3000, Leuven, Belgium., Feys S; Department of Microbiology, Immunology and Transplantation, Laboratory for Clinical Infectious and Inflammatory Disorders, KU Leuven, 3000, Leuven, Belgium., van de Veerdonk FL; Department of Internal Medicine, Radboud University Medical Center, 6525, Nijmegen, Netherlands., Carvalho A; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Guimarães/Braga, Portugal., Naesens L; Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, 3000, Leuven, Belgium., Matthys P; Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Immunobiology, KU Leuven, 3000, Leuven, Belgium., Lagrou K; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Microbiology, KU Leuven, 3000, Leuven, Belgium; Department of Laboratory Medicine and National Reference Center for Mycosis, University Hospitals, Leuven, Leuven, Belgium., Verbeken E; Department of Imaging and Pathology, KU Leuven, 3000, Leuven, Belgium., Chamilos G; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 71300, Heraklion, Crete, Greece; Department of Clinical Microbiology and Microbial Pathogenesis, School of Medicine, University of Crete, Greece., Wauters J; Department of Microbiology, Immunology and Transplantation, Laboratory for Clinical Infectious and Inflammatory Disorders, KU Leuven, 3000, Leuven, Belgium., Humblet-Baron S; Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunity, KU Leuven, 3000, Leuven, Belgium. Electronic address: stephanie.humbletbaron@kuleuven.be., Vande Velde G; Department of Imaging and Pathology, Biomedical MRI Unit/MoSAIC, KU Leuven, 3000, Leuven, Belgium. Electronic address: greetje.vandevelde@kuleuven.be.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2024 Oct; Vol. 108, pp. 105347. Date of Electronic Publication: 2024 Sep 30.
DOI:	10.1016/j.ebiom.2024.105347
Abstrakt:	Background: Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection in critically ill influenza patients that is of incompletely understood pathogenesis. Despite the use of contemporary therapies with antifungal and antivirals, mortality rates remain unacceptably high. We aimed to unravel the IAPA immunopathogenesis as a means to develop adjunctive immunomodulatory therapies. Methods: We used a murine model of IAPA to investigate how influenza predisposes to the development of invasive pulmonary aspergillosis. Immunocompetent mice were challenged with an intranasal instillation of influenza on day 0 followed by an orotracheal inoculation with Aspergillus 4 days later. Mice were monitored daily for overall health status, lung pathology with micro-computed tomography (μCT) and fungal burden with bioluminescence imaging (BLI). At endpoint, high parameter immunophenotyping, spatial transcriptomics, histopathology, dynamic phagosome biogenesis assays with live imaging, immunofluorescence staining, specialized functional phagocytosis and killing assays were performed. Findings: We uncovered an early exuberant influenza-induced interferon-gamma (IFN-γ) production as the major driver of immunopathology in IAPA and delineated the molecular mechanisms. Specifically, excessive IFN-γ production resulted in a defective Th17-immune response, depletion of macrophages, and impaired killing of Aspergillus conidia by macrophages due to the inhibition of NADPH oxidase-dependent activation of LC3-associated phagocytosis (LAP). Markedly, mice with partial or complete genetic ablation of IFN-γ had a restored Th17-immune response, LAP-dependent mechanism of killing and were fully protected from invasive fungal infection. Interpretation: Together, these results identify exuberant viral induced IFN-γ production as a major driver of immune dysfunction in IAPA, paving the way to explore the use of excessive viral-induced IFN-γ as a biomarker and new immunotherapeutic target in IAPA. Funding: This research was funded by the Research Foundation Flanders (FWO), project funding under Grant G053121N to JW, SHB and GVV; G057721N, G0G4820N to GVV; 1506114 N to KL and GVV; KU Leuven internal funds (C24/17/061) to GVV, clinical research funding to JW, Research Foundation Flanders (FWO) aspirant mandate under Grant 1186121N/1186123 N to LS, 11B5520N to FS, 1SF2222N to EV and 11M6922N/11M6924N to SF, travel grants V428023N, K103723N, K217722N to LS. FLvdV was supported by a Vidi grant of the Netherlands Association for Scientific Research. FLvdV, JW, AC and GC were supported by the Europeans Union's Horizon 2020 research and innovation program under grant agreement no 847507 HDM-FUN. AC was also supported by the Fundação para a Ciência e a Tecnologia (FCT), with the references UIDB/50026/2020, UIDP/50026/2020, PTDC/MED-OUT/1112/2021 (https://doi.org/10.54499/PTDC/MED-OUT/1112/2021), and 2022.06674.PTDC (http://doi.org/10.54499/2022.06674.PTDC); and the "la Caixa" Foundation under the agreement LCF/PR/HR22/52420003 (MICROFUN). Competing Interests: Declaration of interests SF declares having received travel support for conference attendance by Pfizer and Gilead, and a speaker fee from The Healthbook Company Ltd. JW declares having received investigator-initiated grants, speakers’ fees and travel support by Pfizer and Gilead, outside the scope of this manuscript. The other authors declare no competing interests. (Copyright © 2024. Published by Elsevier B.V.)
Databáze:	MEDLINE
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