Accelerating our ability to understand and fight the immunopathology caused by respiratory infections with emerging viruses: from mouse models to macaques to patients

"Type I interferons (IFN-I) are key cytokines in antiviral defense. However, if excessive or chronic, their production can contribute to pulmonary immunopathology caused by influenza virus or coronaviruses. Treatment with glucocorticoids induces strong immunosuppression exposing patients to increased viral replication or superinfections. More specific treatments could be achieved by manipulating IFN-I production or activity. This involves determining which cellular sources and functions of IFN-I are deleterious versus beneficial. IFN-I is produced by plasmacytoid dendritic cells (pDC), infected cells and also monocytes/macrophages. pDC produce high levels of IFN-I, without being infected, thus escaping inhibition by viral immune evasion genes. pDC are therefore considered crucial for antiviral defense. However, in human and murine infections with influenza or SARS-CoV2, the role of IFN-I and pDC is debated. This controversy stems from the lack of adequate tools to target pDC specifically and effectively. We have overcome this bottleneck by generating mice that are constitutively and specifically devoid of pDC, and by exploiting them for conditional inactivation of genes in pDC. These innovative approaches demonstrated a deleterious role for pDC in influenza and COVID19 in mice, probably as a result of the fact that pDC production of IFN-I/III occurs too late and is prolonged. Based on these robust preliminary results, the UNFIRE project will pursue three main objectives. (1) To confirm that late/prolonged production of IFN-I/III by pDC is deleterious to the host during respiratory infections with emerging influenza viruses and coronaviruses. To this end, we will extend our studies to other experimental conditions in mice, with two other influenza virus strains, and in models of SARS-CoV2 infection that better reflect viral tropism and pathology as characterized in humans. We will also analyze the role of pDC in the pathophysiology of SARS-CoV2 infection in macaques. Finally, we will compare interferon responses between immunocompetent patients with moderate and severe COVID19 to investigate whether any of their characteristics correlate with disease severity. (2) To determine the cellular and molecular mechanisms underlying the deleterious effects of pDC and IFN-I, by comparing the IFN-I response/reactivity profile of different cell types isolated (i) from the infected lungs or central nervous system in the presence/absence of pDCs (mice, macaques), or (ii) from the blood of COVID19 patients with mild versus severe COVID-19 which differ in the dynamics of their IFN-I responses (human). (3) To identify target molecules/biological pathways and pharmacological drugs that can specifically inhibit IFN-I/III production by pDC or late IFN-I/III responses, in new preclinical mouse models of respiratory viral infections and in human cell cocultures, with the perspective to evaluating the safety and efficacy of the most promising treatments in mice and then in macaques. Our project will contribute to a better understanding of the mechanisms controlling the development of severe pulmonary immunopathology during respiratory viral infections, opening up new avenues for manipulating inflammation for the benefit of the host."