What is The Molecular Mechanism of COVID-19?
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What is The Molecular Mechanism of COVID-19?
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What is The Molecular Mechanism of COVID-19?
Breaking the Mystery of COVID-19 Deaths! Scientists have discovered that the COVID-19 virus infects immune cells through abortive infection, triggering inflammation and causing a cytokine storm.
Since the outbreak of the COVID-19 pandemic over 4 years ago, the virus continues to wreak havoc globally. According to statistics, nearly 7 million people have died from COVID-19 infection worldwide.
Interestingly, the direct cause of progression to severe illness or death in most patients infected with COVID-19 is not the virus itself, but the excessive activation of the inflammatory response and cytokine storm triggered by the virus. However, it is still unclear why the COVID-19 virus can trigger such a strong inflammatory response in our lungs.
Recently, scientists from the University of Southern California published a groundbreaking research in the prestigious journal *Nature Cell Biology*. They found that compared to other RNA viruses, the COVID-19 virus can cause a stronger inflammatory response. Surprisingly, the cytokine storm caused by COVID-19 infection is not due to the rapid replication infection of the virus in early stages in lung epithelial cells, but rather from the “abortive infection” of a large number of infiltrating immune cells in the lungs in the late stage!
More importantly, the researchers also revealed the mechanism by which the COVID-19 virus infects immune cells and triggers cytokine storms. It turns out that Toll-like Receptor 1 (TLR1) on the surface of immune cells can recognize the structural proteins E (envelope glycoprotein) and M (matrix protein) of the COVID-19 virus, leading to the internalization of the virus by immune cells and subsequently causing “abortive infection.” In addition, the binding of the COVID-19 virus envelope glycoprotein E to immune cell TLR1 can directly activate the inflammatory response of immune cells, thereby causing the massive release of pro-inflammatory cytokines. This is the fundamental reason why the COVID-19 virus triggers a cytokine storm!
Dr. Tianhao Duan, Dr. Changsheng Xing, and Dr. Junjun Chu from the Keck School of Medicine at the University of Southern California are the co-first authors of the paper. Professor Rongfu Wang is the corresponding author of the paper.
To understand why the COVID-19 virus is different from other viruses and can trigger such a strong inflammatory response, scientists screened the 27 proteins encoded by the COVID-19 virus. They were surprised to find that a protein encoded by the COVID-19 virus called NSP14 can directly promote the phosphorylation of an important kinase complex IKK in the inflammatory signaling pathway, significantly enhancing the inflammatory response.
Interestingly, they also found that another protein encoded by the COVID-19 virus called ORF6 can inhibit the inflammatory response, and this ORF6 protein can anchor on the cell membrane.
Further experiments showed that the COVID-19 virus’s ORF6 can significantly inhibit the activation of the inflammatory response by blocking the nuclear entry of the inflammatory transcription factor NF-κB.
However, this raised a question for scientists: NSP14 promotes the inflammatory response, ORF6 inhibits the inflammatory response, so is the ultimate result pro-inflammatory or anti-inflammatory?
At this point, scientists speculated that since there is not much inflammation in the early stages of COVID-19 virus infection, but inflammation begins to occur in the middle and late stages of infection, do these two proteins encoded by the COVID-19 virus have different expression patterns during infection, leading to the clinical observations?
At the same time, scientists further discovered that in the late stages of COVID-19 virus infection, there is a large infiltration of immune cells in the lungs of patients. This has led to another speculation: whether in the late stage of infection, these immune cells infiltrating into the lungs can be infected by the COVID-19 virus, leading to the production of a large number of cytokines?
To answer these two questions, scientists conducted a series of experiments. They used a modified COVID-19 virus labeled with green fluorescent protein to infect both lung epithelial cells and immune cells. The results showed that only lung epithelial cells showed a fluorescent signal, while immune cells showed no fluorescence at all. This indicates that the COVID-19 virus can only replicate when infecting epithelial cells, but cannot replicate when infecting immune cells (abortive infection).
In contrast, scientists could only detect a low level of activation of the inflammatory response in lung epithelial cells, while a very strong activation of the inflammatory signal was detected in immune cells.
At this point, scientists suddenly thought, could it be that the different expression patterns of NSP14 and ORF6 in lung epithelial cells and immune cells lead to the suppression of the inflammatory response in epithelial cells and the activation of the inflammatory response in immune cells? Is there any connection with the “abortive infection” of the COVID-19 virus in immune cells?
It is well known that lung epithelial cells are one of the main targets of the COVID-19 virus because there is a key receptor protein called ACE2 on the surface of lung epithelial cells, which can bind to the spike protein S of the COVID-19 virus, thereby facilitating the virus to invade cells. However, immune cells do not have the ACE2 receptor, so they are generally not thought to be infected by the COVID-19 virus.
However, further research by scientists revealed that immune cells can be infected by the COVID-19 virus, but because immune cells lack the key receptor called ACE2, this leads to the inability of the COVID-19 virus to replicate after entering immune cells (abortive infection). Even more surprising, scientists found that this “abortive infection” would selectively express the pro-inflammatory protein NSP14, rather than the anti-inflammatory protein ORF6, after infection of immune cells, leading to the further amplification of the inflammatory response of immune cells, and the production of a cytokine storm.
Therefore, in the early stages of infection, the COVID-19 virus mainly infects lung epithelial cells through the ACE2 receptor on the surface of lung epithelial cells. At this time, the virus rapidly replicates in lung epithelial cells and releases a large number of virus particles to infect other epithelial cells. Although lung epithelial cells also express a small amount of the TLR1 receptor and can be activated by the virus, the level of inflammatory signal activation is very weak. In addition, because the COVID-19 virus can express a large amount of the inflammatory suppression protein ORF6 in epithelial cells, the inflammatory response is further suppressed. Therefore, the early stage of COVID-19 virus infection is mainly characterized by virus replication, with only a mild inflammatory response, which is what we usually call the asymptomatic infection period.
Secondly, in the late stage of COVID-19 virus infection, the virus load reaches its peak, virus replication begins to decline, and immune cells are recruited to the lungs in large numbers. Immune cells recognize and bind to the viral structural proteins E and M, which are highly expressed on the surface of immune cells, leading to the activation of a severe inflammatory response. At the same time, the virus bound to TLR1 can be internalized into immune cells. This “abortive infection” pattern prevents the virus from forming a replication transcription complex (RTC) to transcribe the virus’s subgenomic RNA. Due to the lack of subgenomic RNA, the virus’s structural proteins, including ORF6, are unable to express, but the pro-inflammatory protein NSP14 can be translated
directly through genomic RNA. Because only NSP14 is expressed without ORF6 expression, the inflammatory response is further amplified, immune cells release a large number of cytokines, and a cytokine storm occurs.
Finally, scientists also studied other human coronaviruses in the coronavirus family. They found that SARS-CoV-1 also triggers a large inflammatory response through the same molecular mechanism as SARS-CoV-2. Moreover, the ability of the E protein of SARS-CoV-1 to induce immune cells to produce inflammation is even higher than that of the E protein of SARS-CoV-2. This also explains why the mortality rate of SARS-CoV-1 was as high as 11% when it broke out 20 years ago, much higher than the current SARS-CoV-2.
In contrast, other milder human coronaviruses, such as OC43, NL63, and 229E, have much weaker binding abilities to the TLR1 receptor with their E proteins. This also explains why the symptoms caused by their infection are usually milder.
In summary, this study reveals for the first time at the cellular molecular level the complete molecular mechanism of the COVID-19 virus from entering the human body for replication to triggering severe inflammatory responses in the late stage, leading to severe illness or death! This will provide important theoretical guidance for the treatment of severe COVID-19 patients. Moreover, this study also found that TLR1 small molecule inhibitors may be a better choice for the treatment of severe COVID-19 patients.
What is The Molecular Mechanism of COVID-19?
References:
Duan T, Xing C, Chu J, et al. ACE2-dependent and -independent SARS-CoV-2 entries dictate viral replication and inflammatory response during infection. Nat Cell Biol. 2024. doi:10.1038/s41556-024-01388-w
(source:internet, reference only)
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