Spatial Profiling of Lung SARS-CoV-2 and Influenza Virus Infection Dissects Virus-Specific Host Responses and Gene Signatures

Abstract

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). Robust blood biomarkers that reflect tissue damage are urgently needed to better stratify and triage infected patients. Here, we use spatial transcriptomics to generate an in-depth picture of the pulmonary transcriptional landscape of COVID-19 (10 patients), pandemic H1N1 (pH1N1) influenza (5) and uninfected control patients (4). 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 with few areas of high viral load and these were largely only associated with an increased type I interferon response. A very limited number of genes were differentially expressed between the lungs of influenza and COVID-19 patients. Specific interferon-associated genes (including IFI27) were identified as candidate novel biomarkers for COVID-19 differentiating this COVID-19 from 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.

IFI27 transcription is an early predictor for COVID-19 outcomes; a multi-cohort observational study

“…This indicated that IFI27 expression was part of an intrapulmonary immune response against SARS-CoV-2. This finding was validated by several recently published studies (18)(19)(20), which not only confirmed the upregulation of IFI27 expression in infected lung tissue of COVID-19 patients, but also showed that IFI27 was the most consistently expressed host response gene across all studies (Figure 1D).…”

“…D) Upset plot describing the overlapping gene sets across 5 studies. The size of the gene set varies across the studies with a small number of common genes including IFI27 shared across all studies (18)(19)(20). E) IFI27 gene expression in nasopharyngeal samples in Cohort 2 (n=137).…”

“…IFI27 expression is associated with the severity of several different viral illnesses including respiratory syncytial virus (RSV) infection and Enterovirus 71 (EV71) hand foot and mouth disease [6,7]. Preliminary evidence suggests that IFI27 expression may be a useful biomarker for COVID-19 diagnosis and severity [8][9][10][11]. In the respiratory tract, IFI27 expression is significantly upregulated by SARS-CoV-2 infection, more so than by other respiratory viruses [8,9].…”

“…Preliminary evidence suggests that IFI27 expression may be a useful biomarker for COVID-19 diagnosis and severity [8][9][10][11]. In the respiratory tract, IFI27 expression is significantly upregulated by SARS-CoV-2 infection, more so than by other respiratory viruses [8,9]. IFI27 is also upregulated in the peripheral blood of COVID-19 patients [10,11] and may serve as a biomarker for pre-symptomatic SARS-CoV-2 infection [12].…”

The Effects of COVID-19 on the Placenta During Pregnancy

“…These spatiotemporal relationships in the inflammatory cascade give rise to positive or negative prognoses, and their understanding can triage patients at greater or lesser risks of infection, of response to infection, and inform new therapeutics and treatment regimens ( 106 ). Spatial immunoprofiling is rapidly advancing due to several recent technologies: advanced instrumentation, molecular barcoding and immunolabelling, providing a much richer portrait of the immune landscape ( 107 ), and recent approaches in biostatics and theoretical biology are incorporating imaging data to deconstruct the relationships between cells and disease within their tissue context ( 108 – 110 ). Spatial resolved transcriptomics are changing the ways in which we interrogate complex tissues and were voted the ‘Method of the Year 2020’ by the journal Nature Methods ( 111 ).…”