The inflammatory character of SARS-CoV-2 infection is something the virus requires rather than something it fails to suppress

Status lab-led Areas Pandemic Host Response and Disease, Innate Immune Signaling and the Interferon Response

In the first weeks of 2020 there was no matched description of what SARS-CoV-2 does to a host cell. Blanco-Melo 2020 placed the virus alongside SARS-CoV-1, MERS-CoV, influenza A virus, human parainfluenza virus 3 and respiratory syncytial virus in the same systems and repeated the question at four levels of biological system. The recurring pattern was low type I and type III interferon with only a subset of interferon-stimulated genes induced, alongside pronounced chemokine and interleukin 6 expression, reproduced in cell lines, primary bronchial epithelium, ferrets, post-mortem lung and patient serum. Ruxolitinib abolished interferon-stimulated gene induction while leaving chemokine induction largely intact, which is the direct evidence that the inflammatory arm does not require interferon signalling, and interferon beta pretreatment restricted the virus, so the low output is not resistance.

Reading that imbalance as a failure of viral control assumes the virus would suppress the cytokine arm if it could. Nilsson-Payant 2021 on the NF-kappa B footprint tested the opposite. The dominant early signature in ACE2-expressing A549 cells was tumour necrosis factor alpha signalling through NF-kappa B, with no interferon signature and no STAT1 or IRF3 phosphorylation, concentrated by single-cell sequencing in infected rather than bystander cells, with chromatin accessibility opening at sites enriched for REL, RELA and NFKB1 motifs at distal regulatory elements. Silencing RelA reduced and silencing NF-kappa B1 abolished nucleocapsid protein, and RELA knockout cells were rescued by a chimeric RelA DNA-binding domain fused to a VPR activator while the equivalent IRF3 construct restricted the virus, which places the requirement at the level of NF-kappa B-driven transcription rather than the protein itself. Four chemically distinct inhibitors reduced infection in vitro.

What is now known is that the inflammatory arm of this infection is a viral dependency, which makes replication and inflammation potentially the same target rather than opposing ones. What is not known is which NF-kappa B target genes the virus requires, and whether the dependency holds in an animal, since the authors state they could not reproduce the inhibitor effect in their hamster model and note the absence of approved NF-kappa B inhibitors. No viral product responsible for the low interferon phenotype is identified anywhere in this corpus, and Blanco-Melo 2020 declines to adjudicate between an antagonist overcome at high multiplicity and high multiplicity generating patterns that may not form physiologically. Its human tissue analysis rests on two post-mortem COVID-19 lungs against two healthy lungs and its serum study on 24 cases and 24 controls, comparison viruses were run at differing multiplicities and durations, and the claim that this pattern drives COVID-19 pathology is an interpretation of correlated observations rather than a demonstrated causal chain.

Substantiated by - Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19, establishes the imbalanced response across six viruses and four levels of system and separates the interferon and chemokine arms experimentally - The NF-κB Transcriptional Footprint Is Essential for SARS-CoV-2 Replication, shows that infection engages NF-kappa B and not the interferon factors and that NF-kappa B-driven transcription is required for replication

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