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Ex vivo human precision\u2010cut lung slices (PCLSs) are well\u2010suited models to study immune reactions and biochemical changes within host cells as well as to follow functional macrophage phenotype plasticity within complex tissue environment. Raman spectroscopy emerged in recent years as a powerful method for label\u2010free cell characterization.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human PCLSs from one donor were infected with either the SARS\u2010CoV\u20102 delta or omicron variant. Immunofluorescence microscopy localized AMs and virus particles. Cytokine levels of interferon\u2010gamma (IFN\u2010\u03b3) and interleukin 18 (IL\u201018) were quantified. The lung slice model was optimized for label\u2010free Raman spectroscopic imaging and for the characterization of single AMs within the three\u2010dimensional structure of the PCLS model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Fluorescence microscopy confirmed the location of AMs and virus particles within the PCLS model. Raman spectroscopic imaging generated false\u2010colour images, revealing distinct spectroscopic differences between AMs in the uninfected control PCLS model and those in PCLS models infected with SARS\u2010CoV\u20102. These differences included variations in intracellular RNA, carotenoid, triacyl glyceride, and glucose levels, consistent in interpretation with cytokine quantification data. A linear discriminant analysis (LDA) classification model achieved an 83% accuracy in distinguishing cells from infected lung slices from those of the uninfected controls. The LDA loadings pointed to spectral bands that had been previously identified in an in vitro stimulation study of macrophages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Raman spectroscopy can characterize the cellular immune response and phenotype plasticity of AMs to infection with SARS\u2010CoV\u20102 within a PCLS model in a label\u2010free and non\u2010invasive manner. The ability to distinguish cells from infected PCLSs from cells of the uninfected control PCLS based on intracellular biochemical changes highlights the potential of Raman spectroscopy as a powerful diagnostic tool in immunology and clinical diagnostics.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70453","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T05:55:13Z","timestamp":1756706113000},"source":"Crossref","is-referenced-by-count":2,"title":["Investigating alveolar macrophages in an human ex vivo precision\u2010cut lung slice model of SARS\u2010CoV\u20102 infection using Raman spectroscopy\u2014A case study"],"prefix":"10.1002","volume":"15","author":[{"given":"Max","family":"Naumann","sequence":"first","affiliation":[{"name":"Leibniz Institute of Photonic Technology, Member of Leibniz Health Technologies Member of the Leibniz Centre for Photonics in Infection Research (LPI)  Jena Germany"},{"name":"Center for Sepsis Control and Care (CSCC) Jena 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