Corona virus

Corona virus

In this drawing, the American scientist and artist David Goodsell (3𣛩25. David S. Goodsell 3𣛩346.) Shows 3𣛩27 trapped in the lungs. coronavirus SARS-CoV-2 - more precisely, one of its viral particles, or virion . It could penetrate the lungs with an inhalation as part of an aerosol released into the air when an infected person sneezes or coughs, or from the upper respiratory tract if the virus settled and multiplied there first (while actively transmitting to other people).

The viral particle was surrounded by protective proteins of the intercellular space of the lungs - mucins (3-3-3335. Mucins 3-3-33346.), 3-3-3337. interferons 3-3-33346. , immunoglobulins and others. Their task is to prevent the virus from infecting a new cell. The task of the virus is to load its genome into the cell (while the virion is destroyed) and force it to collect new viral particles. In SARS-CoV-2 the genome carrier is one long RNA molecule (depicted as a bluish-white ribbon). It is covered in many copies of protein N (blue in the picture). Together they are surrounded by a lipid membrane (white), in which three proteins are embedded in different amounts - S, spike protein (pink), M (light orange) and E (also pink, as the artist decided). Squirrel E in the virion is the least - can you find it in the picture? If not, here is her signed version (and if you want to color the virus differently, on the website David Goodsell, you can download the coloring). Proteins S, M, E, and N are called "structural" because they form a virion. All coronaviruses have them (and some also have a fifth structural protein). Other proteins that will be needed to assemble the virus in the cell are encoded in the RNA of the virus, but they do not enter the virion - therefore, they are not shown in the figure.

The most prominent coronavirus protein is the S-protein (spike protein). It is he who is responsible for the penetration of coronavirus into the cell. And it is thanks to the spikes- peplomeres forming a halo around a viral particle, under a microscope resembling solar corona , coronaviruses got their name. (However, the spike itself, formed by three S-proteins, also looks like a corona, only an ordinary one, not a salty one. But this turned out, of course, later.)

Corona virus

Colorized SARS-CoV-2 photograph taken on transmission electron microscope . The crown of thorns (3-3-33349. Red 3-3-33350.) Is clearly visible. Photo from the National Institute of Allergy and Infectious Diseases (3-3-3373. NIAID 3-3-33346.) From 3-3-375.

The virion diameter is 120160 nm, excluding spikes, and the spike length is 20 nm. SARS-CoV-2 is almost two orders of magnitude smaller than the cells that it infects.

Corona virus

A cell (3-3-33349. Green 3-3-33350.) Surrounded by SARS-CoV-2 virions (3-3-33349. Pink 3-3-33350.). Numerous cell outgrowths indicate that it is at the final stage of apoptosis - programmed cell death - and will soon be fragmented. Infection of the cell with the virus is one of the reasons for apoptosis. Colorized photograph obtained using a scanning electron microscope from the site

Infection of the cell begins with the fact that the virus, with the help of spikes from the S-protein, attaches itself to the molecules sticking out of the cell membrane. angiotensin converting enzyme 2 (ACE2 or ACE2 - from the English. 3-3-3115. Angiotensin-converting enzyme 2 3-3-33346.). It has long been known that ACE2 is expressed in the cells of the lungs, blood vessels, heart, kidneys, intestines (which is probably why diarrhea occurs among the symptoms of COVID-19). But only this year it became clear that ACE2 is also present on the surface of epithelial cells of the upper respiratory tract and eyes, albeit in a smaller amount. S-protein SARS-CoV-2 binds to ACE21020 times stronger than than the similar protein of its relative and predecessor SARS-CoV , the causative agent of SARS. Perhaps this is why the new virus can actively multiply in the upper respiratory tract, which makes it more contagious. Indeed, when propagating in cells at the border with the external environment, the virus is more easily transmitted to other people than when it is produced in the lungs.

Corona virus

This spatial model of the tenon (side and top views) is assembled on the basis of 3207 images obtained by cryoelectron microscopy. One of the three S-proteins in the spike is shown in colored ribbons . The ACE2 binding site ( RBD , Receptor binding domain) is shown green . This site spontaneously 揾ides and 揺xposes to the surface of the tenon, and in the two remaining S-protein molecules it is just 揾idden (3-3-33349. RBD down 3-3-33350.). Image from article D. Wrapp et al., 2020.3-3r3147. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

The ACE2 enzyme is an important component of the so-called angiotensin-renin hormonal system . Normally, he 揷atches and inactivates the peptide hormone angiotensin . In blood vessels, ACE2 helps lower blood pressure, and in the lungs, it soothes the inflammatory response that occurs in response to tissue damage. It turns out that the virus not only exploits cells, but also violates the protection mechanism tissues. Perhaps this contributes to the severity of lung damage in patients with COVID-19.

Corona virus

SARS-CoV-2 bound to ACE2 (cyan) on the cell surface. Three-dimensional illustration from the site

Binding of the virus to ACE2 triggers the process in the cell. endocytosis : at the point of contact with the virus, the cell membrane is pressed into the cell until a bubble forms around the virus. Inside this membrane vesicle is endosomes - The virus enters the cell. A cell uses endocytosis to absorb large molecules, which are then cleaved and used as raw materials for the synthesis of the substances it needs. Therefore, endosomes have their own 揹igestive enzymes - proteases that cut proteins, recognizing specific amino acid sequences. On one of the external chains of the S-protein there is just a section that such enzymes cut. The virus is just waiting for this: 揻usion peptides (fusion peptides, see Lipid bilayer fusion ) Are amino acid chains that can invade the endosome membrane. A shortened S-protein, connected at one end to the virus membrane and the other to the endosome membrane, folds, attracting the membranes to each other. As a result, the virus membrane merges with the endosome membrane, their integrity is violated, and all contents - including the virus genome - are thrown out into the cytoplasm of the cell.

From that moment on, the cell is already infected, and the 揟rojan horse that delivered the strand of viral RNA into it the virion with its S-protein crown and three other proteins played a role and the virus no longer needed. Now the cell itself will begin to do what the virus has invaded into it - to produce copies of its RNA and proteins and to collect new virus particles from them. But while the cell does not have the apparatus necessary for this: it can build RNA on a DNA matrix (transcription) and proteins on an RNA matrix (translation), but it cannot "multiply" RNA. The next stage in the life cycle of a virus is the assembly of such an apparatus. More precisely, its self-assembly from proteins that the cell will build on viral RNA.

At the very beginning of this RNA (at the 5'-end, see 5'-end ) There are molecular structures characteristic of messenger RNA cells. Therefore, cellular protein synthesis systems - ribosomes - take the RNA of the virus for their own and爐hey collect a long chain of amino acids on its matrix, while reading about two-thirds of the viral genome. This long chain, the ORF1ab polyprotein, is cut into 16 non-structural (i.e., not forming a virion) proteins. Among them there are cell scissors - proteases; they are still in the general chain correctly fold and begin to work. It is they who cut the chain into individual proteins - it turns out that the polyprotein cuts itself.

Corona virus

For a detailed account of the proteins encoded by the SARS-CoV-2 virus, see the popular New York Times article. Bad News Wrapped in Protein: Inside the Coronavirus Genome . The diagram from this article shows how the genes of non-structural, structural, and auxiliary proteins are located on the RNA of the virus from its beginning (left) to the end of 3-3-33351.

Due to the fact that the precursors of SARS-CoV-2 which are very similar to it and also caused dangerous epidemics, have been actively studied, we already know a lot about its non-structural proteins. Some of them trick the cell抯 defense mechanisms, while others block the assembly of its own proteins. But most importantly, is assembled from several non-structural proteins. RNA-dependent RNA polymerase (RNA replicase) is a protein complex that can synthesize RNA by RNA (and not by DNA, as is usually the case in a cell). RNA replication is performed in two stages, each of which is similar to transcription DNA strings in RNA. First, by the principle of complementarity of On the matrix of genomic RNA, 揳ntigenomic RNA is synthesized, which already serves as a matrix for new genomic RNA.

Viral RNA polymerases are often mistaken and insert the wrong nucleotides into the RNA - that is, they introduce mutations. This helps RNA-containing viruses to evolve quickly, however, due to the high frequency of mutations, they cannot afford to have a long genome and a lot of proteins - something will break down all the time. Therefore, the average length of viral RNA genomes is only 9000 nucleotides. But coronaviruses are an exception: the length of their genomes reaches 30000 nucleotides. This is due to the fact that coronaviruses have a unique protein for RNA viruses that can cut off the newly attached nucleotide from the synthesized chain if it is not complementary to the matrix. This helps to reduce the percentage of errors in the synthesis of new RNA molecules.

Corona virus

The coronavirus RNA polymerase complex consists of several non-structural proteins (3-3-33349. Nsp 3-3-33350., From the English 3-3-33349. Non-structural proteins 3-3-33350.). Nsp12 (polymerase proper) is an enzyme that synthesizes RNA from the RNA matrix. Nsp7 and nsp8 synthesize a seed for polymerase (3𣛩349. Primer 3𣛩350.), With which the synthesis of a new RNA chain begins. Nsp14 with the assistance of nsp10 controls how neatly the polymerase works. Nsp9 keeps the matrix chain unfolded until polymerase arrives. Scheme from an article by E. C. Smith and M. R. Denison, 2013.3-3r3249. Coronaviruses as DNA Wannabes: A New Model for the Regulation of RNA Virus Replication Fidelity

Like all polymerases, viral polymerase replicates RNA back-to-back: not from the beginning (5'-end), but from the end (from the 3'-end, see 3'-end ). Thus, replication begins just from that third of the genome, according to which no proteins were collected at the first stage. In the process of synthesis of the 揳ntigenomic chain, RNA polymerase passes through special regulatory nucleotide sequences located between the protein genes. From each of these regulatory sequences, it is with some probability that it can 搄ump to the very end of its path along the matrix, skipping everything else. If this happens, shortened 揳ntigenomic matrices are formed, along which the so-called subgenomic mRNA is then assembled. It has a 5'-end with the standard start of messenger RNA, then all non-structural protein genes (and some structural ones) are skipped, and genes from the end of the viral RNA go immediately. Since there are several regulatory sequences capable of causing a jump in the last third of the genome, several different subgenomic RNAs are also obtained. All of them end the same way, and (if you look from the end), the shorter ones are embedded in longer ones, and all together - in complete RNA. Nested - in English nested (literally translated, 3-3-33349. form a nest 3-3-33350.); It is with this feature that the name of the detachment, which includes the coronaviruses: is associated. Nidoviruses 3-3-33350. ([i] Nidovirales ), From lat. nidus "nest".

Subgenomic RNA serve matrix for the production of four structural proteins (S, E, M, and N) and several other auxiliary proteins, see the diagram above. Auxiliary proteins are not part of the virion. Some of them interact with the body抯 immune system or help ready-made virions leave the cell; the functions of others are not yet clear. It is known that in the laboratory the virus does not need them for reproduction, and in the body they are simply necessary.

Only one or two proteins are translated from each subgenomic RNA, after which the translation stops (the following proteins are already translated from their subgenomic RNA). This allows the virus to clearly adjust quantitative ratio of produced proteins: it is determined by the probabilities with which RNA polymerase jumps from their genes to the beginning of the genome.

Full copies of viral RNA launch new circles of virus replication: new copies of non-structural proteins are read from them, from which RNA polymerases are again collected. They, in turn, generate new copies of the viral genome and new matrix subgenomic RNAs, through which cell ribosomes synthesize viral proteins. Thus, everything necessary for the assembly of new viral particles accumulates in the cell. It remains for us to understand how they form and leave the cell.

Corona virus

SARS-CoV coronavirus life cycle (SARS-CoV-2 has the same). Virion penetrates the cell by endocytosis; then the S-protein is cleaved, as a result of which the viral and endosome membranes fuse and RNA emerges. The first two-thirds of the genome are translated into polyproteins (1ab or shortened 1a). They are cut (3𣛩349. Proteolysis 3𣛩350.) Into the non-structural proteins from which the viral RNA polymerase is assembled (3𣛩349. Replicase 3𣛩350.). Using it, (3𣛩349. Transcription of 3𣛩350.) Copies of the virus RNA and eight types of subgenomic mRNA are formed templates for generating structural and auxiliary proteins in the lumen (3𣛩349. ERGIC 3𣛩350.) Between the endoplasmic reticulum (3𣛩350. Golgi apparatus . Virions collect in the cytoplasm and exit the cell by 3-3-3305. exocytosis . Scheme from article 3-3-3307. Computer technology against coronavirus: first results 3𣛩346. (An unadapted scheme is in L. Du et al., 2009. 3-3-3309. The spike protein of SARS-CoV - a target for vaccine and therapeutic development 3-3-33346.) 3-3-33351.

Proteins S, M and E are membrane. Like membrane proteins the cell itself, they are synthesized by ribosomes associated with endoplasmic reticulum 3-3-33346. (EPR) - organelle, which is a collection of membrane cavities. Using special molecular complexes, proteins are introduced into the EPR membrane directly during its elongation. Then a part of the membrane with new proteins is budded from the EPR, the resulting transport vesicle goes to the outer cell membrane and subsequently merges with it.

Viral proteins embedded in the membrane of the vesicle can float along its surface and come together, so that they form a 搈osaic. The molecules of protein M, binding to each other, form a dense lattice in the wall of the bubble. Along the way, also binding to M, copies of proteins E and S are included in the lattice. The latter combine in three and form spikes looking inside the vesicle. As the transport vesicle travels through the cell, numerous copies of protein N surrounding the genomic RNA of the virus bind to the cytoplasmic regions of the M proteins. All these interactions lead to the lattice closing around the viral RNA, and the finished viral particle with a fresh crown around it is inside the transport vesicle. And when the bubble merges with the cell membrane, the virus is outside.

Corona virus

SARS-CoV-2 virions are released from one of the cells in a laboratory culture. Electronic micrograph from

As you can see, we are dealing with a very interesting virus. Despite this, I would like to wish everyone not to get to know him personally!

Figure David S. Goodsell from .

Galina Klink

22 爨 2020 /
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项躅骅 眍忸耱

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