SARS-CoV-2‘s Viral Proteins Incapacitates Human Host Cells And Disables Cell’s Warning System Of Pathogenic Intrusion Confirms Latest Study
’s viral proteins according to a new study led by researchers from California Institute of Technology and involving scientist from University of Southern California, University Of Vermont, University of California-Los Angeles, University of Glasgow and Broad Institute of MIT and Harvard, are able to incapacitate human host cells upon invasion and are further able to disarming the cellular warning system of pathogenic intrusion.
To date there is still no proper understanding of the molecular basis of SARS-CoV-2 pathogenesis.
In this research, involving the study of 30 SARS-CoV-2 proteins, the study team comprehensively defines the interactions between SARS-CoV-2 proteins and human RNAs. In summary, the study found that the 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. Lastly, the NSP8 and NSP9 proteins 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.
The study results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses.
The research findings are published in the journal: Cell https://www.cell.com/cell/pdf/S0092-8674(20)31310-6.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420313106%3Fshowall%3Dtrue
Physicians and researchers have a fairly good idea of what the main symptoms of the COVID-19 disease look like: cough, fever, shortness of breath, and fatigue, among others. However equally critical to treating symptoms is understanding what the coronavirus that causes COVID-19, SARS-CoV-2, is doing inside human cells to make individuals so sick.
Similar to the modus operandi of most viruses, SARS-CoV-2 breaks into a cell and hijacks its resources and machinery to create more viruses. Evolutionarily speaking, successful viruses are those that can effectively evade a cell's defenses, but refrain from killing the cell outright (This is important as the virus needs the cell to remain alive to be able to reproduce).
Typically human cells and, more broadly, mammalian cells have built-in defense mechanisms to deal with viral infections. The presence of viral genetic material in a cell triggers a cascade of events that lead to the production and secretion of a group of proteins called interferon, which will try to shut down the infection and notify neighboring cells of the threat.
Scientists have found that patients with severe COVID-19 symptoms also show low levels of interferon response, suggesting that the interferon response is crucial for combatting the virus.
However the key questions have been how does the virus suppress these normal defense mechanisms?
team in this research has now pinpointed the mechanisms through which the SARS-CoV-2 virus incapacitates human cells, essentially disabling the cell's alarm system so that it cannot call for help or warn nearby cells of the infection. Understanding how the virus causes dysfunction at the cellular level gives new insights into how to fight it.
The study was conducted primarily in the laboratory of Dr Mitchell Guttman, professor of biology and Heritage Medical Research Institute investigator.
It was found that the SARS-CoV-2 virus produces about 30 viral proteins.
In the study, the team examined each of these and mapped out how they interact with the molecular components within human cells grown in a lab dish.
Interestingly the team found that SARS-CoV-2 proteins attack three critical cellular processes to disrupt human protein production.
Dr Emily Bruce, faculty scientist at the University of Vermont and a co-first author on the paper told Thailand Medical News, "Viruses are amazing. Viruses and host cells are continually in an evolutionary arms race to outwit one another. SARS-CoV-2 has evolved intricate and specific ways to disable cells without killing them outright, so that the virus can still use the cell for its own purposes."
The human cell's nucleus houses its genetic material, written as DNA. This so-called genome can be thought of as a comprehensive instruction manual, with "chapters" that might be titled "How to Send a Signal" or "What to Do in Case of Viral Infection," for example. The rest of the cell contains the machinery that creates the proteins (such as interferon) that carry out these instructions.
Importantly the process for turning DNA instructions into useful proteins is called the "central dogma" of biology. The first step is transcription, through which a piece of DNA in the cell's nucleus is read and copied into a form (a molecule called mRNA) that can leave the nucleus and travel to the rest of the cell. Before export out of the nucleus, mRNA is often re-assembled and "matured" in a process called splicing (top row).
When the mRNA is exported out of the nucleus, a piece of cellular machinery called the ribosome attaches to the mature mRNA, reads it, and builds the corresponding protein through a process called translation (middle row).
Certain of these proteins are designed to move outside the cell of origin to transmit messages to other cells, for example, to warn about the presence of a viral infection. In this situation, another piece of cellular machinery called the signal recognition particle comes into play; it works as a kind of transport system that helps proteins move from inside to outside of a cell. This is known as protein trafficking (bottom row).
A graphic of healthy cellular protein production (left column), compared to how SARS-CoV-2 disrupts these
processes (right column). The virus disrupts the processes of splicing, translation, and protein trafficking
in order to prevent the cell from calling for help during an infection. Credit: Inna-Marie Strazhnik / Caltech
The study team discovered that SARS-CoV-2 proteins interfere with this whole process at multiple stages. Some of the virus's proteins prevent mRNA from being fully spliced and properly assembled. Others plug up the ribosome so that it cannot form new proteins.
More important other SARS-CoV-2 proteins interfere with the signal recognition particle and block protein transport.
The SARS0Cov viral protein that plugs up the ribosome is called NSP1. Remarkably, the team found, NSP1 blocks human mRNA from entering the ribosome, but allows viral mRNA to pass through just fine.
Viral mRNA contains a genetic signature at the beginning of each of its mRNAs that acts like an access code that effectively hijacks the ribosome to make viral proteins but not human proteins. Because viral production depends on this signature, it could represent a potent target for anti-viral therapeutic development.
Dr Guttman explained, "Each of the processes that SARS-CoV-2 disrupts ie splicing, translation, and protein trafficking is so important for converting the human genetic material into proteins, and they are essential for human biology. These are machines that are central to life. We cannot exist without them. SARS-CoV-2 has evolved in very specific ways to disable these cellular machines and disrupt their functions."
Co-first author Dr Abhik Banerjee, a graduate student in the Guttman laboratory added, "Our research illustrates the importance of basic science research, and establishes a pipeline to address newly emerging RNA viruses in the future."
He further added, "This research additionally llustrates the collaborative atmosphere of science at Caltech and elsewhere in the scientific community at its best. Here at Caltech, we have access to leaders in several keystone areas of biology, including professors Dr Rebecca Voorhees (co-author on the published manuscript), Dr Bil Clemons, and Dr Shu-ou Shan in structural biology, all of whom were willing to discuss ramifications of our data and provide expertise in this relatively new area for us."
Dr Mario Blanco, a research scientist in the Guttman laboratory, agrees.
He commented, "Our ability to interrogate the human RNA targets of SARS-CoV-2 proteins allowed us to identify these mechanisms without prior evidence. The methods and practices we developed here will allow us to apply these same processes to emergent diseases and even currently existing viruses where we lack a deep understanding of mechanism."
The team concluded that disruption of these three non-overlapping steps of protein production may represent a multipronged mechanism that synergistically acts to suppress the host antiviral response. Specifically, the IFN response is usually boosted >1,000-fold upon viral detection, yet each individual mechanism impacts IFN levels on the order of ~5-10-fold.
Accordingly, if each independent mechanism impacts IFN levels moderately, the three together may be able to achieve dramatic suppression of IFN (103 =1,000- fold). This multi-pronged mechanism may explain the molecular basis for the potent suppression of IFN observed in severe COVID-19 patients.
Interferon is emerging not only as a determinant of disease severity, but also a potential treatment option. As such, this study identifies several therapeutic opportunities for boosting IFN levels upon SARS-CoV-2 infection. For example, disrupting the interaction between NSP1 and 18S rRNA could allow cells to detect and respond to viral infection. Because many small-molecule drugs target ribosomal RNAs, it may be possible to develop drugs to block the NSP1-18S and other interactions. Additionally, disrupting the 5’ viral leader may be a potent antiviral strategy since it is critical for translation of all viral proteins. Because SL1 is a structured RNA, it may be possible to design small molecules that specifically bind this structure to suppress viral protein production. Viral suppression of these cellular functions is not exclusive to the IFN response and will also impact other spliced, translated, secreted, and membrane proteins.
Many proteins involved in anti-viral immunity are spliced and/or membrane-anchored or secreted. For example, class I major histocompatibility complex (MHC), which is critical for antigen presentation to CD8 T cells at the cell surface of infected cells. By antagonizing membrane trafficking, SARS-CoV-2 may prevent viral antigens from being presented on MHC and allow infected cells to escape T-cell recognition and clearance.
In this way, interference with these essential cellular processes might further aid SARS-CoV-2 in evading the host immune response. More generally, the study team expects that insights gained from the SARS-CoV-2 protein-RNA binding maps will be critical for exploring additional viral mechanisms.
Specifically, the team identified many other interactions, including highly specific interactions with mRNAs. For example, NSP12 binds to the JUN mRNA which encodes the critical immune transcription factor cJun which is activated in response to multiple cytokines and immune signaling pathways. The study also identified an interaction between NSP9 and the start codon of the mRNA that encodes COPS5, the enzymatic subunit of the COP9 Signalosome complex which regulates protein homeostasis, suggesting that it might disrupt its translation.
Interestingly, COPS5 (also known as JAB1) is known to bind and stabilize c-Jun protein levels and several viruses are known to disrupt this protein.
Together, the study findings demonstrate that global mapping of RNA binding by viral proteins could enable rapid characterization of mechanisms for emerging pathogenic RNA viruses.
For the latest on SARS-CoV-2
, keep on logging to Thailand Medical News.