Evolution of enhanced innate immune evasion by SARS-CoV-2

Abstract

The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6—all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection4. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants.

Executable network of SARS-CoV-2-host interaction predicts drug combination treatments

“…The mechanistic explanations from our model advance the fight against the COVID-19 pandemic by increasing our understanding of why some treatments work and others fail. Our model and screening are readily accessible and are built using the BMA opensource and freely available toolset (https://biomodelanalyzer.org) and can be updated as new SARS-CoV-2 variants emerge that may exploit different mechanisms to enter cells and replicate or suppress host defence mechanisms 16 .…”

“…By contrast, a delayed or absent IFN-I/III response to infection may contribute to the presentation of severe disease 7,[9][10][11][12][13][14][15] . This is especially of concern as emerging variants have adapted to allow potent host immune antagonism 16 , allowing the virus to replicate with little opposition in the early stages of infection 1,10 . This can then be followed by a maladaptively strong and persistent inflammatory response only after the majority of viral replication has occurred 9,17 , leading to life-threatening conditions such as acute respiratory distress syndrome (ARDS) 18 .…”

SARS-CoV-2 learned the ‘Alpha’bet of immune evasion

“…Phosphoproteomics analysis revealed curtailed activities of these kinases early during infection with Alpha 1 , consistent with low IFN and ISG induction. Conversely, activation of these kinases at a later time was higher in cells infected with Alpha than in cells infected with the earlier isolates 1 , suggesting intricate mechanisms of kinase dysregulation by Alpha. However, defining the role of temporal kinase regulation in viral pathogenesis and the involvement of viral proteins and their regulation (as described below for Orf9b) requires further exploration.…”

“…By contrast, the role of mutations outside the spike protein in virus pathogenesis remains scarcely explored. In Nature, Krogan and colleagues 1 crack the code of non-spike mutations found in the Alpha variant of SARS-CoV-2 by showing that some of these mutations ramp up the expression of viral innate immune antagonists, allowing escape from intrinsic immune defenses.…”

“…By mining viral RNA sequencing and proteomics data, Krogan and colleagues find that Alpha produced greater amounts of sgRNA and sgRNA-encoded proteins such as Orf9b, Orf6 and nucleocapsid (N) than did earlier virus isolates 1 . This enhanced production is likely due to nucleotide changes that alter the transcriptional and/ or translational regulation of Orf9b and N 1 . Future work is needed to fully determine the mechanism(s) behind boosted sgRNA synthesis.…”