TYPE-I INTERFERON MODULATION in VIVO BLOCKS SARS-CoV-2 REPLICATION and INFLAMMATION

ABSTRACT

Background: Systemic and local inflammation following SARS-CoV-2 infection has been widely described and predictive of disease severity and death. However, the exact immune mediators driving inflammation contributing to SARS-CoV-2 host defense vs. those driving immune-mediated pathology in humans have not been fully elucidated. Deficiencies in type-I interferon (IFN-I) responses, including inborn errors to genes in the IFN-I pathway, neutralizing auto-antibodies against all subtypes of IFN-I, or the lack of production of IFN-I, are associated with severe COVID-19 in otherwise healthy individuals. Conversely, sustained IFN-I responses have been shown to contribute to severe COVID-19 by exacerbating inflammation, and prolonged IFN-I signaling has been shown to interfere with lung repair following viral infection and to increase susceptibility to bacterial infections. Thus, it is critical to understand the roles of IFN-I signaling in COVID-19 to design therapeutic strategies. Methods: Here, we modulated IFN-I signaling in rhesus macaques (Macaca mulatta;RMs) from day-1 through day 2 post SARS-CoV-2 infection (dpi) using an IFN-I antagonist (IFNant). Eighteen RMs (9 control and 9 IFNant treated) were infected with SARS-CoV-2 on day 0, with 6 RMs sacrificed at 2, 4, and 7dpi. Nasal and throat swabs were collected for viral load;blood and bronchoalveolar lavage fluid (BAL) for flow cytometry and RNAseq. Results: IFNant treatment prior to infection resulted in a highly significant and consistent reduction in SARS-CoV-2 viral load in the lower airways (>3-log difference;2dpi BAL) and upper airways (nasal and throat swabs). Treatment with IFNant initiated also potently reduced (i) soluble markers of inflammation in BAL, (ii) expansion of inflammatory monocytes (CD14+CD16+), and (iii) pathogenesis in the lung. Furthermore, Siglec-1 expression, which has been shown to enhance SARS-CoV-2 infection, was rapidly downregulated in the lung and in monocytes of IFNant-treated RMs. Remarkably, RNAseq analysis showed a robust reduction in pathways associated with inflammation and decreased levels of interferon-stimulated genes post-infection in treated RMs. Thus, IFNant treatment prior to infection resulted in limited viral replication, inflammation, and pathogenesis in SARS-CoV-2-infected RMs. Conclusion: These data indicate a vital, early role of IFN-I in regulating COVID-19 progression and emphasize the importance of understanding IFN-I pathways in COVID-19 for the development of targeted therapeutic strategies.