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

We studied the host transcriptional response to SARS-CoV-2 by performing metagenomic sequencing of upper airway samples in 234 patients with COVID-19 (n=93), other viral (n=100) or non-viral (n=41) 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, macrophages, and increased proportions of goblet, dendritic and B-cells, compared to other viral ARIs. Using machine learning, we built 27-, 10- and 3-gene classifiers that differentiated COVID-19 from other acute respiratory illnesses with AUCs of 0.981, 0.954 and 0.885, 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. Comparing host transcriptional response to SARS-CoV-2 infection versus response to other respiratory viral infection or non-viral acute respiratory infection. **RAW DATA NOT PROVIDED DUE TO PATIENT PRIVACY CONCERNS**