Profiling of lung SARS-CoV-2 and influenza virus infection dissects virus-specific host responses and gene signatures.

Kulasinghe, Arutha; Tan, Chin Wee; Dos Santos Miggiolaro, Anna Flavia Ribeiro; Monkman, James; SadeghiRad, Habib; Bhuva, Dharmesh D; da Silva Motta Junior, Jarbas; Vaz de Paula, Caroline Busatta; Nagashima, Seigo; Baena, Cristina Pellegrino; Souza-Fonseca-Guimaraes, Paulo; de Noronha, Lucia; McCulloch, Timothy; Rodrigues Rossi, Gustavo; Cooper, Caroline; Tang, Benjamin; Short, Kirsty R; Davis, Melissa J; Souza-Fonseca-Guimaraes, Fernando; Belz, Gabrielle T; O'Byrne, Ken

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that 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. Here, we use targeted transcriptomics of FFPE tissue using the Nanostring GeoMXâ„¢ platform to generate an in-depth picture of the pulmonary transcriptional landscape of COVID-19, pandemic H1N1 influenza and uninfected control patients. 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. 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.