Role of type I Interferons and plasmacytoid dendritic cells in the lung immunopathology caused by respiratory viral infections – RIPIREVI

Type I interferons (IFN-I) are key cytokines in vertebrate antiviral defense. However, if excessive or chronic, their production can contribute to the pulmonary immunopathology caused by respiratory infections with influenza (Flu) or coronaviruses. Treatment with glucocorticoids induces a broad immunosuppression at the risk of increased viral replication or susceptibility to other infections. More specific treatments may be achieved by selective manipulation of IFN-I production or responses. This implies determining the deleterious versus beneficial cellular sources and functions of IFN-I. IFN-I can be produced from infected cells and plasmacytoid dendritic cells (pDC). pDC produce high levels of all IFN-I, without being infected therefore escaping inhibition by viral immune evasion genes. Therefore, pDC are considered to be crucial for antiviral defense. Yet, in human and mouse infections with Flu or SARS-CoV2, whether IFN-I and their production by pDC are beneficial or deleterious is debated. This controversy is in part due to lack of tools for specific and penetrant targeting of pDC. We have overcome this bottleneck by generating pDC-less mice, constitutively and specifically lacking pDC, and harnessing them for conditional gene inactivation in pDC. These innovative approaches enabled us demonstrating a deleterious role of pDC in Flu and Covid19. To understand the underlying mechanisms, we will: 1) determine how pDC contribute to severe immunopathology during Flu infection, 2) test whether viral restriction by Mx1 mitigates IFN-I/pDC deleterious effects in Flu infection, and 3) dissect how IFN-I protects against SARS-CoV2 despite pDC redundant/deleterious functions. Our project will contribute characterizing cellular and molecular actors contributing to the hyperactivation/misfiring of IFN-I responses causing severe lung immunopathology during respiratory viral infections, hence providing novel levers to manipulate immune responses to promote health.