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). 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 GeoMX™ 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.

Transcriptomic profiling of cardiac tissues from SARS‐CoV‐2 patients identifies DNA damage

“…Transcriptomic analysis of patient myocardial tissue offers a unique opportunity to understand the mechanisms of SARS‐CoV‐2 and IAV‐induced cardiac complications. Specifically, spatial transcriptomics that consider intra‐organ heterogeneity [ 42 , 43 ], provide a powerful tool for characterizing host responses to respiratory viral infections outside of the respiratory tract. Here, we use targeted spatial transcriptomic characterization of myocardial tissue to generate an in‐depth picture of the myocardial transcriptional landscape of COVID‐19, pandemic H1N1 influenza and uninfected control patients and shed light on the mechanisms that might drive these different clinical outcomes (Figure 1 ).…”

Transcriptomic profiling of cardiac tissues from SARS-CoV-2 patients identifies DNA damage

“…Transcriptomic analysis of patient myocardial tissue offers a unique opportunity to understand the mechanisms of SARS-CoV-2 and IAV induced cardiac complications. Specifically, spatial transcriptomics that consider intra-organ heterogeneity 42,43 , provide a powerful tool for characterising host responses to respiratory viral infections outside of the respiratory tract. Here, we use targeted spatial transcriptomic characterisation of myocardial tissue to generate an in-depth picture of the myocardial transcriptional landscape of COVID-19, pandemic H1N1 influenza and uninfected control patients and shed light on the mechanisms that might drive these different clinical outcomes.…”

An Evolutionary Insight Into the Heterogeneous Severity Pattern of the SARS-CoV-2 Infection

“…Type 1 IFNs comprise the largest class that exhibit varied binding affinity with the IFNAR1/2 receptor complex and as a result diversified anti-viral responses are induced and amplified in the host ( Moraga et al, 2009 ). In a recent cohort-based study, pulmonary tissue samples from the severely affected patients of COVID-19 and pH1N1 influenza showed differential expression of two genes, IFI27 and IFI6, both belonging to type 1 IFNs ( Kulasinghe et al, 2021 ). The findings for differential expression of the IFN genes controlling the immunoregulatory responses have also been corroborated in transcriptomic profiling of the hospitalized COVID-19 patients ( Ahern et al, 2021 ).…”