Interplay between SARS-CoV-2 and the type I interferon response

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.

Imperfect innate immune antagonism renders SARS-CoV-2 vulnerable towards IFN-γ and -λ

“…Our analysis indicates that during a SARS-CoV-2 infection less cytokines than expected are released, autophagic turnover is blocked and general immune activation is perturbed. This is supported by a large amount of data from COVID19 patients [24][25][26][27][28]45,62,[71][72][73] . However, an important question remains: Why are some innate immune pathways, such as IFN-γ signaling less antagonized (Fig.…”

Inhibition of SARS-CoV-2 polymerase by nucleotide analogs: a single molecule perspective

“…Furthermore, under certain conditions, the interferon α-induced viperin converts up to 30% the cellular pool of CTP into ddhCTP, further increasing its stoichiometry and favoring its potency 30 . This may explain why SARS-CoV-2 viral proteins inhibits the interferon response 33 . ddhCTP therefore represents an exciting viral replication inhibitor with a low cytotoxicity and high efficacy.…”

Vitamin D and SARS-CoV-2 infection—evolution of evidence supporting clinical practice and policy development

“…Reports have suggested that SARS-CoV-2 infection is associated with an absent or delayed type I IFN response and an exacerbated release of proinflammatory cytokines [47]. It is known that the SARS-CoV-2 virus encodes at least 10 proteins that allow the virus to inhibit, evade, or counteract the effects of type I IFNs [48]. In a small study by Trouillet-Assant et al, Covid-19 patients who failed to produce a detectable type I IFN response were significantly more likely to require invasive ventilation [49].…”