According to WHO data, although the immunity generated by vaccines, drugs and previous infections has enabled more and more people to avoid severe COVID-19, the coronavirus has caused more than 6 million deaths, and the real death toll may exceed 18 million.
Some virologists are worried that COVID-19 will continue, and SARS-CoV-2 may experience a massive epidemic once or more each year, just like adenovirus and other coronaviruses that cause the common cold. One of the keys to the success of this virus is its ability to neutralize the body's immune response, which is attributed to the virus's protein library.
The fierce battle between the virus and the host
In the past three years, researchers have begun to explore these virus responses. They have shown that many SARS-CoV-2 molecules have managed to protect the virus from host immunity, allowing the invading virus to replicate and spread to more people.
When the novel coronavirus (SARS-CoV-2) invades fragile human cells and converts human cells into a virus production factory, a fierce battle broke out between the virus and the host.
When the spike protein on the virus attaches to the target of the cell, this invasion will trigger an alarm, triggering a comprehensive counterattack from the multi-pronged immune system.
The attacked cells begin to release an effective immune protein called Interferon , the protein can enhance its resistance to coronavirus.
alarm
Attacked cells begin to release a powerful immune protein called interferon (blue), thereby enhancing resistance to coronavirus. Interferon promotes the expression of hundreds of immune-related genes that can hinder every step of the viral infection cycle.
Find and destroy
Interferon also contacts receptor on various immune cells , recruiting them into the body's struggle with the virus. Certain immune sentries, called T cells (blue), hunt and destroy infected cells (grey), reducing the production of more viruses.
Once immune cells called CD8-positive T cells detect signs of SARS-CoV-2, they hunt and destroy infected cells in the body, reducing the production of new viruses.
blocks the virus
B cells that block the immune system is also activated and secretes proteins called antibodies that target viral proteins such as spikes (red). These antibodies stare at the viral particles, locking them out of the cells. However, as the virus replicates, their spikes may mutate, resulting in versions that evade this neutralizing antibody. For example, the current SARS-CoV-2 variant can avoid many antibodies produced by the original COVID-19 vaccine or previous infection.
Another immune cell called B cells begins to produce large quantities of antibodies, fixing the virus particles outside the cells.
viruses often defeat these defense systems.
As the virus replicates rapidly in millions of people, its spike protein has mutated, allowing the virus to escape neutralizing antibodies caused by vaccines or previous infections.
Like many viruses, SARS-CoV-2 is good at blocking, evading, and tricking our immune system in other ways.
"Viruses usually have arms races with their hosts," said Adriana Forero, a viral immunologist at Ohio State University School of Medicine. The virus's strategy of evading the immune system makes people unable to help but is amazing .
multifunctional virus protein
SARS-CoV-2’s struggle with the immune system is a set of multifunctional proteins that force infected cells to use their RNA code for production.
SARS-CoV-2 begins to build its protein library by delivering a string of RNA (its genome) into the cells.
The virus has less than 15 recognized genes (colors) — also known as open reading frames — but the amino acids strings they encode are cleaved into more proteins.For example, ORF1a produces 11 so-called nonstructural proteins (Nsp1-11).
Once the virus uses the cell's own mechanism to translate its genes into proteins, some proteins - spikes , membrane, nucleocapsid, envelope - continue to form the structure of the new virus. Most viral proteins still roam around cells, operating their functions in their respective ways or destroying the immune system.
researchers still have differences on the number of protein species contained by viruses infected with cells, with an estimated range of 26 to 30, but SARS-CoV-2 contains more viral proteins than most other RNA viruses . For example, Ebola virus contains only 7 proteins.
To explore how specific SARS-CoV-2 proteins break our immune defenses, researchers produce these protein molecules in cells through genetically modified technology. The researchers then classified the effects of cells responding to these protein molecules, such as interferon output.
These studies show that most proteins in the viral library play an immune-suppressing role—including membrane protein that helps new viral particles assemble, and editing enzymes that cut freshly synthesized protein into small pieces.
However, not all of these features have been proven.
Perlman said that just overproduction of one viral protein may not trigger the same cellular effects as the natural infection of the virus.
To verify this discovery, experiments on the virus itself need to be carried out, genetically adjusted to make it lack a single protein. But researchers rarely conduct such studies because such studies require detailed biosafety precautions.
virologist Susan Weiss and colleagues recently found in a study on MERS-CoV that immunosuppressive proteins may also rely on partnerships with one or more other viral molecules. MERS-CoV is a virus that causes Middle East Respiratory Syndrome , which is similar to SARS-CoV-2.
SARS-CoV-2 virus destroys interferon response
SARS-CoV-2 virus will greatly destroy the body's interferon response, and the interferon response is the core of our resistance to viruses.
interferon can initiate hundreds of immune-related genes, hindering every step of the virus infection cycle.
Some genes strengthen the external defense of cells, allowing them to resist viruses trying to invade.
Other genes enhance the internal defense of infected cells, inhibiting the production of viral molecules or preventing them from assembling into new viral particles.
also has some interferon-stimulated genes that prevent newborn viruses from leaving infected cells.
Interferon also helps recruit T cells and B cells to participate in the human body's battle with viruses. The study conducted by
in patients with COVID-19 has once again confirmed the importance of interferon in the fight against SARS-CoV-2.
For example, a considerable proportion of severe patients with have defects in interferon response.
Researchers found that up to 20% of the most severe patients carry antibodies, which attach to their own interferons, causing them to lose their function.
Many other pathogens, including viruses that cause influenza , Ebola and Hepatitis C , all target interferon responses.
But Freiro said SARS-CoV-2's ability to disrupt interferon response is particularly prominent. "What is unusual is the level of comprehensiveness of this virus."
SARS-CoV-2 viral proteins can disrupt multiple steps, including cell monitoring of viral RNA, delivering alarm signals to nucleus , synthesizing interferons and activate genes that activate interferon stimulation.
In addition, the study found that coronavirus, various proteins can block the same step.
SARS-CoV-2 Virus Protein Library
Some SARS-CoV-2 proteins bypass the interferon response by camouflage.
For example, the non-structural protein 15 (Nsp15) can cut out unique sequences from newly synthesized viral RNA molecules, helping to hide these RNAs so that they are not discovered by cell pathogen detectors and avoid triggering the production of interferons.
and even some proteins that mainly play a structural role have added a process of disrupting the interferon reaction.
For example, the daily work of nucleocapsid proteins is to package the RNA of the pathogen into the interior of the viral particle. But a study this year showed that a cellular enzyme can cut nucleocapsid proteins into pieces, preventing infected cells from producing interferon.
However, SARS-CoV-2 not only blocks the interferon response. It may also hinder other immune defenses.
For example, some studies have shown that viral proteins such as ORF3a, ORF7a and envelope proteins hinder the process known as autophagy . During autophagy, infected cells digest their own contents, breaking down viruses and individual viral proteins in the process.
SARS-CoV-2 may also interfere with MHC-I, MHC-I is a protein that displays invader fragments on the surface of infected cells and summons T cells.
MHC-I and MHC-II signaling pathways
Viral proteins such as ORF6 and ORF8 may inhibit the cell production of MHC-I or prevent its transfer to the cell surface, thereby preventing T cells from recognizing and killing infected cells.
viral protein has dual or triple functions
Nsp14 is a typical example of a multifunctional viral protein molecule.
Like many other proteins of viruses, Nsp14 performs some tasks that are not related to immune evasion.
It works with Nsp10 to help viruses reproduce by correcting errors in newly synthesized copy of viral RNA genomes.
Nsp14 also binds to other proteins including Nsp9 and Nsp12, labeling RNA with molecular caps, so that the ribosome of the cells synthesize proteins can read RNA and produce large quantities of viral proteins.
But Immunologist Jack Chun-Chieh Hsu and colleagues in 2021 revealed another important function of Nsp14: This molecule in some way prevents infected cells from producing the cell's own protein.
Xu Zhenjie said this blockade may force cells to transfer their resources to make viral proteins, thus benefiting SARS-CoV-2.
Nsp14 may also prevent cells from starting interferon-stimulating genes. This is an important strategy to combat the production of these antiviral proteins. Another viral protein of
SARS-CoV-2 Nsp1 seems to induce similar immune blocking effects by interfering with ribosomes, preventing ribosomes from producing proteins of the host cell itself.
However, scientists are still unclear: why cells are still able to produce viral proteins when viruses prevent ribosomes from producing cellular proteins. How to deal with SARS-CoV-2? researchers deal with the virus by understanding the mechanisms of SARS-CoV-2 resisting the cellular immune system. Several research groups have screened existing compounds and drugs with anti-Nsp15 activity. However, so far, no one has developed drugs specifically designed to block the anti-immune effects of SARS-CoV-2. Pfizer drug combination is nirmatrevir and ritonavir (ritonavir), which is widely known as Paxlovid. It targets an viral enzyme Nsp5 with immunosuppressive properties, but the company's goal is to block the central role of this protein in SARS-CoV-2 replication. Scientists have not fully understood SARS-CoV-2's strategy to evade human defense. As the epidemic delays, scientists' research is becoming more and more in-depth. To ensure that you can receive every article, please add attention! Welcome to recommend me to your family and friends~
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