Coronavirus Disease-19 (COVID-19) symptoms range from mild to severe illness. The cause for this differential response to infection remains unknown. Unravelling the immune mechanisms acting at different levels of the colonization process might be key to understand these differences.

Our study aims at understanding the differential immune response that leads to different disease COVID-19 severities.

We carried out a multi-tissue gene expression study of immune-related genes (>500) in blood, nasal, and saliva samples, collected on asymptomatic, mild, and severe patients and healthy controls (156 samples in total) through the Nanostring technology.

Our results point to a set of genes that are tissue-specific and correlated to severity, mainly involved in the innate response and cytokine signalling. Nasal epithelium showed a robust activation of the antiviral machinery in mild cases, characterized by IFN pathway involvement, successfully controlling the infection at local level. Instead, severe cases showed these IFN response switched off; they develop an innate response represented by an over-expression of genes related to monocyte-macrophage recruitment in nasal epithelium. We did not find signals of immune viral response in buccal mucosa in mild patients, which probably indicates a successful local control of the infection. However, buccal mucosa in moderate and, to a greater extent, severe cases, provided evident signals of viral activity, cell arresting and viral dissemination to the lower respiratory tract, ultimately generating an exacerbated innate and impaired adaptative systemic immune responses in blood.

Local immune response could be key to determine the course of the systemic response.