Kulasinghe, A.Tan, C.W.Ribeiro Dos Santos Miggiolaro, A.F.Monkman, J.SadeghiRad, H.Bhuva, D.D.Motta Junior, J.D.S.Busatta Vaz de Paula, C.Nagashima, S.Baena, C.P.Souza-Fonseca-Guimaraes, P.de Noronha, L.McCulloch, T.Rossi, G.R.Cooper, C.Tang, B.Short, K.R.Davis, M.J.Souza-Fonseca-Guimaraes, F.Belz, G.T.et al.2022-06-242022-06-242022European Respiratory Journal, 2022; 59(6):1-190903-19361399-3003https://hdl.handle.net/2440/135620BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in late 2019 has spread globally, causing a pandemic of respiratory illness designated coronavirus disease 2019 (COVID-19). A better definition of the pulmonary host response to SARS-CoV-2 infection is required to understand viral pathogenesis and to validate putative COVID-19 biomarkers that have been proposed in clinical studies. METHODS: Here, we use targeted transcriptomics of formalin-fixed paraffin-embedded tissue using the NanoString GeoMX platform to generate an in-depth picture of the pulmonary transcriptional landscape of COVID-19, pandemic H1N1 influenza and uninfected control patients. RESULTS: Host transcriptomics showed a significant upregulation of genes associated with inflammation, type I interferon production, coagulation and angiogenesis in the lungs of COVID-19 patients compared to non-infected controls. SARS-CoV-2 was non-uniformly distributed in lungs (emphasising the advantages of spatial transcriptomics) with the areas of high viral load associated with an increased type I interferon response. Once the dominant cell type present in the sample, within patient correlations and patient-patient variation, had been controlled for, only a very limited number of genes were differentially expressed between the lungs of fatal influenza and COVID-19 patients. Strikingly, the interferon-associated gene IFI27, previously identified as a useful blood biomarker to differentiate bacterial and viral lung infections, was significantly upregulated in the lungs of COVID-19 patients compared to patients with influenza. CONCLUSION: Collectively, these data demonstrate that spatial transcriptomics is a powerful tool to identify novel gene signatures within tissues, offering new insights into the pathogenesis of SARS-COV-2 to aid in patient triage and treatment.en©The authors 2022. This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions@ersnet.orgCOVID-19HumansInfluenza A Virus, H1N1 SubtypeInfluenza, HumanInterferon Type ILungSARS-CoV-2LungHumansInterferon Type IInfluenza, HumanInfluenza A Virus, H1N1 SubtypeCOVID-19SARS-CoV-2Journal article10.1183/13993003.01881-20212022-06-24614500Bhuva, D.D. [0000-0002-6398-9157]Davis, M.J. [0000-0003-4864-7033]