Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. An unbalanced immune response, characterized by a weak production of type I interferons (IFN-Is) and an exacerbated release of proinflammatory cytokines, contributes to the severe forms of the disease. SARS-CoV-2 is genetically related to SARS-CoV and Middle East respiratory syndrome-related coronavirus (MERS-CoV), which caused outbreaks in 2003 and 2013, respectively. Although IFN treatment gave some encouraging results against SARS-CoV and MERS-CoV in animal models, its potential as a therapeutic against COVID-19 awaits validation. Here, we describe our current knowledge of the complex interplay between SARS-CoV-2 infection and the IFN system, highlighting some of the gaps that need to be filled for a better understanding of the underlying molecular mechanisms. In addition to the conserved IFN evasion strategies that are likely shared with SARS-CoV and MERS-CoV, novel counteraction mechanisms are being discovered in SARS-CoV-2–infected cells. Since the last coronavirus epidemic, we have made considerable progress in understanding the IFN-I response, including its spatiotemporal regulation and the prominent role of plasmacytoid dendritic cells (pDCs), which are the main IFN-I–producing cells. While awaiting the results of the many clinical trials that are evaluating the efficacy of IFN-I alone or in combination with antiviral molecules, we discuss the potential benefits of a well-timed IFN-I treatment and propose strategies to boost pDC-mediated IFN responses during the early stages of viral infection.
Highlights
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta-coronavirus that emerged at the end of 2019 in China and rapidly spread around the world, causing a pandemic [1, 2]
SARS-CoV-2 infection is responsible for COVID-19, a disease associated with mild symptoms in the majority of cases but that can progress to an acute respiratory distress syndrome [1, 3]
Despite being expressed at moderate levels in vitro and in vivo, several up-regulated IFN-stimulated gene (ISG) identified by these transcriptomic studies (Table 2) exhibit well-characterized broad-spectrum antiviral activities and could have additive restrictive effects on SARS-CoV-2 replication
Summary
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta-coronavirus that emerged at the end of 2019 in China and rapidly spread around the world, causing a pandemic [1, 2]. Numerous welldescribed ISGs exhibit direct antiviral activities by targeting specific stages of the viral life cycle, including entry into host cells, replication, protein translation, and assembly of new virus particles. As a first step towards identifying ISGs able to restrict SARS-CoV-2 replication, transcriptomic responses to infection have been analyzed in different cellular models, including primary cells, Table 2.
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