Coronavirus Latest: University Of Texas Health Uncovers How SARS-CoV-2 Virus Camouflages Itself Inside Human Host To Evade Detection By Immune System
: Researchers from University of Texas Health-San Antonio, Texas Biomedical Research Institute-San Antonio and New England Biolabs-Massachusetts have in a new study involving the usage of Advanced Photon Source have discovered new insights into the ways the SARS-CoV-2 virus camouflages itself inside the human body.
Researchers from around the globe have been working for months to identify and develop treatments that inhibit the SARS-CoV-2, the virus that causes COVID-19.
A critical part of that process is understanding how the virus evades detection inside the human body, camouflaging itself to hide from the body's immune system. The SARS-CoV-2 has a few ways of accomplishing this.
The study team team utilizing the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science User Facility at the DOE's Argonne National Laboratory, has revealed insights into the mechanism of one of the many ways the virus uses to elude the immune system.
In SARS coronaviruses, the non-structural protein 16 (nsp16), in conjunction with nsp10, methylates the 5′-end of virally encoded mRNAs to mimic host cellular mRNAs, thus protecting the virus from host innate immune restriction
The study team reports here the high-resolution structure of a ternary complex of SARS-CoV-2 nsp16 and nsp10 in the presence of cognate RNA substrate analogue and methyl donor, S-adenosyl methionine (SAM). The nsp16/nsp10 heterodimer is captured in the act of 2′-O methylation of the ribose sugar of the first nucleotide of SARS-CoV-2 mRNA. It was observed that a large conformational change associated with substrate binding as the enzyme transitioned from a binary to a ternary state. This induced fit model provides mechanistic insights into the 2′-O methylation of the viral mRNA cap. The study team also discovered a distant (25 Å) ligand-binding site unique to SARS-CoV-2, which can alternatively be targeted, in addition to RNA cap and SAM pockets, for antiviral development.
The study findings were published in the journal Nature Communications. https://www.nature.com/articles/s41467-020-17496-8
Dr Yogesh Gupta, Assistant Professor, University of Texas Health Center at San Antonio and the corresponding author on the paper told Thailand Medical News, “The SARS-CoV-2 virus uses the classical mechanism of camouflaging and exploiting the host machinery for its own protein synthesis. It goes inside the host cell and its messenger RNA looks the same as the host messenger RNA.
Dr Gupta added, "A lot of researchers are looking at how the virus enters a cell. We wanted to look at what happens when it is inside the cell. How does the virus survive and evade immune mechanisms?"
In order to do this, Dr Gupta and his team examined two of the SARS-CoV-2 proteins, known as nonstructural proteins 10 and 16, using the ultrabright X-rays generated by the APS. The work was performed at the Northeastern Collaborative Access Team (NE-CAT) beamline, number 24-ID, which is managed by Cornell University.
The study team discovered that the SARS-CoV-2 virus uses some unique ways to camouflage its messenger ribonucleic acid (RNA), the single-stranded molecule that carries the genetic code for synthesizing proteins, to mimic those of the host cell. The immune system cannot differentiate it from the body's own messenger RNA, so it doesn't fight the virus off. The host cell's immune system will treat the virus-like it belongs.
Dr Gupta added, "The virus uses the classical mechanism of camouflaging and exploiting the host machinery for its own protein synthesis. It goes inside the host cell and its messenger RNA looks the same as the host messenger RNA."
Dr Gupta said this process was thought to be similar to those seen in previous coronaviruses, but his team observed some unique features in the SARS-CoV-2 protein.
Detailed understanding how this particular virus uses this protein to avoid detection will help with designing new treatments. What's needed, he said, is a drug that targets the virus, not the host, and knowing more about the camouflage mechanism will help develop one.
The study team also discovered a unique pocket in the structure of the proteins, one that is not present in previous coronaviruses. This pocket, Dr Gupta said, may be a strong target for antiviral development.
NE-CAT is one of 16 beamlines at the APS that have dedicated a significant portion of beam time to COVID-19 research, using a technique called macromolecular crystallography. This involves diffracting X-ray beams off of crystals grown from proteins.
The study team accessed the NE-CAT beamline remotely, operating it through a computer interface. Remote and mail-in experiments have been the focus of the APS since March, as a result of the COVID-19 pandemic.
However scientists using NE-CAT are likely used to the interface, since 95 percent of the beamline's research is carried out remotely, according to Dr Frank Murphy, associate director of NE-CAT and a senior research associate at Cornell.
Dr Murphy added, "The APS is a great place to do photon science and it's the best place in the world to do macromolecular crystallography. We have so many good people and good beamlines."
Dr Gupta's team has been using the APS since 2007, employing various X-ray techniques to uncover insights into biological structures.
Dr Gupta said, "The APS is a unique facility that allows us to measure X-ray diffraction data precisely and quickly. We are fortunate to have a relationship with the APS, and it has allowed us to further our knowledge of the basic mechanisms of this virus."
In conclusion, the stud team had presented here a high-resolution structure of a ternary complex of SARS-CoV-2 RNA cap/nsp16/nsp10 complex captured just prior to ribose 2′-O methylation. The structure also reveals the basis of an ‘induced fit’ model of the RNA cap binding and 2′-O methylation of the first transcribing nucleotide of SARS-CoV-2 genome. Also, the team describes a distantly located ligand-binding site in nsp16/10 capable of accommodating small molecules outside of the catalytic pocket, which may be considered, in addition to SAM- and RNA cap-binding pockets, in the development of antiviral therapies to treat SARS-CoV-2 infections.
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