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Cell: SARS-COV-2 Disrupts Vital RNA functions and suppresses interferon-1 production to interfere with host defenses.

2020-10-26
EM of SARS-COV-2 from Groopman lab

Cell journal published a paper on October 8, 2020 that describes as-yet unknown functions of the SARS-COV-2 virus NSPs (non-structural proteins) 1, 8, 9, and 16. These proteins interfere with messenger ribonucleic acid (mRNA) activity in the host (human) cell and prevent the cell from producing interferon to warn other cells about the COVID-19 infection.

Some basic information about SARS-COV-2 and its proteins: The four proteins that are associated with the virus genome RNA in its native state are nucleocapsid, envelope, membrane, and spike, or for short, N, E, M, and S. These are known as structural proteins. In addition, after the virus gets into the human cell, its RNA codes for RNA polymerase, helicase, and other proteins required for reproduction; these are, in shorthand, NSP (non-structural protein)1 through 16. There are also seven other proteins, labelled ORF (open reading frame) 3a through 8, whose functions are unknown. This makes a total of twenty-seven proteins, four in the virus itself and twenty-three produced after insertion into the host cell.

This article in Cells from May 2020 explains many of the details of the virus replication machinery and its proteins. Don’t read it unless you want to get really deep into the biochemistry of the virus. Just skim this blog post.

When the virus gets into the human cell, the cell detects its presence with proteins in the cytoplasm. There are several of these proteins including TLR7 (which I mentioned in an earlier post) RIG-1, and MDA5, but they all stimulate IRF-3 (interferon regulatory factor), which is specifically designed to detect single-stranded RNA. This protein stimulates the production of interferon. The virus is able to compete by shutting down interferon production, and the paper explains one way that it does this.

The new paper elucidates the functions of four of the virus proteins, as described in the abstract:

NSP16 binds to the mRNA recognition domains of the U1 and U2 splicing RNAs and acts to suppress global mRNA splicing upon SARS-CoV-2 infection. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome and leads to global inhibition of mRNA translation upon infection. Finally, NSP8 and NSP9 bind to the 7SL RNA in the signal recognition particle and interfere with protein trafficking to the cell membrane upon infection. Disruption of each of these essential cellular functions acts to suppress the interferon response to viral infection. Our results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses.

https://doi.org/10.1016/j.cell.2020.10.004

To amplify on the abstract: the protein NSP16 attaches to specialized RNAs (called “spliceosomes”) U1 and U2 that splice new RNA after it is transcribed from DNA in the cell’s nucleus. Normally these RNA-protein complexes modify the RNA by removing introns, leaving the parts that code for a new protein. Inhibiting the “spliceosome” prevents nuclear DNA from producing mRNA that crosses the membrane from the nucleus into the cytoplasm– where it is supposed to be translated into proteins.

The viral protein NSP1 binds to the entrance channel on human ribosomal RNA and prevents human messenger RNA (mRNA) from passing through, which stops mRNA from being translated into a protein. This shuts down the human cell’s protein production facility in the cell cytoplasm.

The virus is apparently still able to produce proteins from its own RNA. It does this because the virus mRNA contains a sequence at its beginning that releases NSP1 and promotes the translation of the rest of the virus mRNA.

The viral proteins NSP8 and 9 bind to RNA-protein complexes that help fold proteins and transfer them to the cell membrane– where they are normally released into the extracellular space and can travel through the blood to distant cells. In the presence of NSP8 and 9, proteins cannot transfer out of the human cell.

The most important human protein affected by these virus is interferon, which would normally signal to other cells that an infection is in process and stimulate the host to defend the system against the infection. In severe COVID-19, there is a notable deficiency of interferon. Many other proteins that the human system uses in defense against viral infections are also affected by this interference.

These virus proteins are produced in the early stages of COVID-19 infection, to prevent the host cell from mounting a defense while it gets to work reproducing itself. The virus RNA is exposed to detection early on in the cell’s cytoplasm and vulnerable to host defenses, but later, during replication, it forms a network to protect itself (this is described in the Cells paper mentioned above.)

The work reported in this new Cell paper is complex and involves the use of human cell lines as well as the SARS-COV-2 virus and mutant viruses. The paper shows how the virus is able to suppress the immune response during early infection and helps to explain some of the effects seen in severe infections.

This work will help us to find treatments that can inhibit the effects of these virus proteins and ameliorate severe infections. We should remain aware that procedures to prevent infection are the most powerful “treatment” for the virus available. This is because not getting infected in the first place gives us a better result than being infected, getting sick, being treated, and surviving.

This means that using face masks (and goggles or clear plastic face shields in high-exposure situations), washing our hands, and staying physically separated from strangers will help more than any treatment. A vaccine will provide an additional barrier against infection, when it is available.

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