Gideon Schreiber Lab

Interferons (IFNs) are essential for defense against viral infections but also drive recruitment of inflammatory cells to sites of infection, a key feature of severe COVID-19. Here, we explore the complexity of the IFN response in COVID-19, examine the effects of manipulating IFN on SARS-CoV-2 viral replication and pathogenesis, and highlight pre-clinical and clinical studies evaluating the therapeutic efficacy of IFN in limiting COVID-19 severity.

Type I and type III interferons (IFNs) are major components in activating the innate immune response. Common to both are two distinct receptor chains (IFNAR1/IFNAR2 and IFNLR1/IL10R2), which form ternary complexes upon binding their respective ligands. This results in close proximity of the intracellularly associated kinases JAK1 and TYK2, which cross phosphorylate each other, the associated receptor chains, and signal transducer and activator of transcriptions, with the latter activating IFN-stimulated genes. While there are clear similarities in the biological responses toward type I and type III IFNs, differences have been found in their tropism, tuning of activity, and induction of the immune response. Here, we focus on how these differences are embedded in the structure/function relations of these two systems in light of the recent progress that provides in-depth information on the structural assembly of these receptors and their functional implications and how these differ between the mouse and human systems.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has substantially diversified during the pandemic, resulting in the successive emergence of variants characterized by various mutations. It has been observed that several epidemic variants, including those classified as variants of concern, share mutations at four key residues (L452R, T478K, E484K, and N501Y) within the receptor binding motif (RBM) region of the spike protein. However, the processes through which these four specific RBM mutations were acquired during the evolution of SARS-CoV-2, as well as the degree to which they enhance viral fitness, remain unclear. Moreover, the effect of these mutations on the properties of the spike protein is not yet fully understood. In this study, we performed a comprehensive phylogenetic analysis and showed that the four RBM mutations have been convergently acquired across various lineages throughout the evolutionary history of SARS-CoV-2. We also found a specific pattern in the order of acquisition for some of these mutations. Additionally, our epidemic dynamic modeling demonstrated that acquiring these mutations leads to an increase in the effective reproduction number of the virus. Furthermore, we engineered mutant spike proteins with all feasible combinations of the four mutations, and examined their properties to uncover the influence that these mutations have on viral characteristics. Our results provide insights into the roles these four mutations play in shaping the viral characteristics, epidemic proliferation, and evolutionary pathway of SARS-CoV-2.