Pulmonary Aspergillosis is a respiratory infection with a high mortality rate, which affects patients with immunosuppression or structural lung defects. Antifungal treatment options are few and many have narrow therapeutic margins and potentially serious side effects. In recent years, there are growing numbers of reports of antifungal resistance. Thus, there is an urgent need for effective models to study fungal pathogenesis and test antifungal therapies in the respiratory system. Here, we present a novel ex-vivo model using precision-cut lung slices in an air-liquid interface platform to evaluate lung tissue responses to fungal infection and antifungal treatment. Readouts assessed were lactate dehydrogenase for tissue damage, release of inflammatory cytokines (TNF-α, IL-1β, CXCL1), and histology for confirmation of hyphal invasion. Overall, the PCLS-ALI model is a promising approach for understanding lung tissue responses to fungal infections, which fulfils the reduction and refinement components of the 3Rs guiding principles for ethical use of experimental animals.
Funding
L.E.G.-H. was supported by the Wellcome Trust – Imperial College London ISSF Training Fellowship in Global Health Research [204834/Z/16/Z] and by the Peruvian National Fund for Scientific Development, Technology and Innovation of the National Science and Technology Council [FONDECYT-Concytec, 118-2017]. T.J.W. was supported by a Strategic Research Centre Award [TrIFIC, SRC015] from the Cystic Fibrosis Trust. CAE was funded by [099951, https://doi.org/10.35802/099951], a Global Health Trials Award with the UK Foreign, Commonwealth and Development Office, the UK Medical Research Council, and the UK Department of Health and Social Care through the National Institute of Health Research award MR/K007467/1]; the National Institutes of Health Fogarty International Center training grant award D43TW010074-07; and research and fellowship funding from the charity IFHAD: Innovation For Health And Development. D.A.J. is funded by the Wellcome Trust (no. 219551/Z/19/Z), the Medical Research Council (grant no. MR/V037315/1) and the Cystic Fibrosis Trust (grant no. SRC015). D.A.J. is funded by the Department of Health and Social Care (DHSC) Centre for Antimicrobial Optimisation (CAMO), Imperial College London. The views expressed in this publication are those of the authors and not necessarily those of the DHSC, National Health Service or National Institute for Health Research (NIHR).
