Upper airway gene expression differentiates COVID-19 from other acute respiratory illnesses and reveals suppression of innate immune responses by SARS-CoV-2

Abstract

We studied the host transcriptional response to SARS-CoV-2 by performing metagenomic sequencing of upper airway samples in 238 patients with COVID-19, other viral or non-viral acute respiratory illnesses (ARIs). Compared to other viral ARIs, COVID-19 was characterized by a diminished innate immune response, with reduced expression of genes involved in toll-like receptor and interleukin signaling, chemokine binding, neutrophil degranulation and interactions with lymphoid cells. Patients with COVID-19 also exhibited significantly reduced proportions of neutrophils and macrophages, and increased proportions of goblet, dendritic and B-cells, compared to other viral ARIs. Using machine learning, we built 26-, 10- and 3-gene classifiers that differentiated COVID-19 from other acute respiratory illnesses with AUCs of 0.980, 0.950 and 0.871, respectively. Classifier performance was stable at low viral loads, suggesting utility in settings where direct detection of viral nucleic acid may be unsuccessful. Taken together, our results illuminate unique aspects of the host transcriptional response to SARS-CoV-2 in comparison to other respiratory viruses and demonstrate the feasibility of COVID-19 diagnostics based on patient gene expression.

Dynamic data-driven meta-analysis for prioritisation of host genes implicated in COVID-19

“…While ACE2 was identified as a host dependency factor in the CRISPR screen, TMPRSS2 was not, and as neither gene was included in the other two screens, the effects (or lack thereof) could not be confirmed. The only other supportive evidence for a role in disease pathophysiology, in studies included here, came from a single transcriptomic study for each; there was no evidence from protein-protein interaction, proteomics or genetics 51,58 . Candidate gene association studies are highly dependent on prevalence of functional variants and, while overlapping to a limited extent with results of large-scale screens included here, have been notably unable to detect significant associations with ACE2 18 .…”

Genetic mechanisms of critical illness in COVID-19

“…Data sources within the same category share the same color (see legend). The largest categories and data sources are labelled: Sun_2020, 79 rosa_2020, 80 zhang_2020, 81 langelier_2020, 82 wei_ 2020, 83 heaton_2020. 84 An interactive version of this figure is available at https://baillielab.net/maic/covid].…”

Dysregulated transcriptional responses to SARS-CoV-2 in the periphery support novel diagnostic approaches

“…Our understanding of immune mechanisms driving the varied acute, recovery, and postinfectious manifestations of COVID-19 continues to evolve 1 . Recent work has demonstrated altered mRNA profiles during SARS-CoV-2 infection at the site of infection -in respiratory epithelial cells, BAL, or nasal swab samples -highlighting the dysregulated immune responses at local sites [2][3][4][5][6] . However, the manner in which these signals are modulated (or propagated) beyond the respiratory microenvironment plays a significant role in the ability of the host to control these responses.…”