Early nasal type I IFN immunity against SARS-CoV-2 is compromised in patients with autoantibodies against type I IFNs.

Lopez, Jonathan; Mommert, Marine; Mouton, William; Pizzorno, Andrés; Brengel-Pesce, Karen; Mezidi, Mehdi; Villard, Marine; Lina, Bruno; Richard, Jean-Christophe; Fassier, Jean-Baptiste; Cheynet, Valérie; Padey, Blandine; Duliere, Victoria; Julien, Thomas; Paul, Stéphane; Bastard, Paul; Belot, Alexandre; Bal, Antonin; Casanova, Jean-Laurent; Rosa-Calatrava, Manuel; Morfin, Florence; Walzer, Thierry; Trouillet-Assant, Sophie

IFN-I and IFN-III immunity in the nasal mucosa is poorly characterized during SARS-CoV-2 infection. We analyze the nasal IFN-I/III signature, namely the expression of ISGF-3-dependent IFN-stimulated genes, in mildly symptomatic COVID-19 patients and show its correlation with serum IFN-α2 levels, which peak at symptom onset and return to baseline from day 10 onward. Moreover, the nasal IFN-I/III signature correlates with the nasopharyngeal viral load and is associated with the presence of infectious viruses. By contrast, we observe low nasal IFN-I/III scores despite high nasal viral loads in a subset of critically ill COVID-19 patients, which correlates with the presence of autoantibodies (auto-Abs) against IFN-I in both blood and nasopharyngeal mucosa. In addition, functional assays in a reconstituted human airway epithelium model of SARS-CoV-2 infection confirm the role of such auto-Abs in abrogating the antiviral effects of IFN-I, but not those of IFN-III. Thus, IFN-I auto-Abs may compromise not only systemic but also local antiviral IFN-I immunity at the early stages of SARS-CoV-2 infection.