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BREAKING NEWS
Source: Coronavirus News  Oct 11, 2020  18 days ago
BREAKING! Coronavirus News: ORF3b Identified As Viral Factor That Impairs Immune Responses In COVID-19 Patients. Alarmingly New Variant Also Found!
BREAKING! Coronavirus News: ORF3b Identified As Viral Factor That Impairs Immune Responses In COVID-19 Patients. Alarmingly New Variant Also Found!
Source: Coronavirus News  Oct 11, 2020  18 days ago
Coronavirus News: A new study led by Japanese researchers from the University of Tokyo along with support by scientist from Hiroshima University, Kyoto University, Tokai University, Ulm University Medical Center-Germany, and University of Glasgow have discovered that ORF3b, a protein encoded by the SARS-CoV-2 is responsible for impairing the immune and interferon responses in COVID-19 patients.


 
According to the study team, one of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in its ORF3b gene.
 
In this study the researchers showed that the SARS-CoV-2’s ORF3b is a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays reveal that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity.
 
In addition analyses of approximately 17,000 SARS-CoV-2 sequences identify a natural variant in which a longer ORF3b reading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction.
 
The study findings not only help to explain the poor interferon response in COVID-19 patients but also describe the emergence of natural SARS-CoV-2 quasispecies with an extended ORF3b gene that may potentially affect COVID-19 pathogenesis.
 
The study findings are published in the peer reviewed journal: Cell.
https://www.cell.com/cell-reports/fulltext/S2211-1247(20)31174-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124720311748%3Fshowall%3Dtrue#%20
 
A key prominent feature that distinguishes COVID-19 from SARS in terms of immune responses is the poor induction of a type I interferon (IFN) response by SARS-CoV-2 compared to SARS-CoV and influenza A virus. Notably, impaired IFN responses are associated with COVID-19 disease. However, the molecular mechanisms underlying the inefficient IFN responses in SARS-CoV-2 infection remain unclear.
 
The study team aimed to characterize the viral factor(s) determining immune activation upon SARS-CoV-2 infection and found that ORF3b, a gene encoded by SARS-CoV-2, is a potent IFN antagonist.
 
Lead scientist, Dr Kei Sato, Associate Professor (Principal Investigator) at Division of Systems Virology, Department of Infectious Disease Control, Institute of Medical Science, the University of Tokyo told Thailand Medical News, "The poor IFN responses in COVID-19 patients may be explained by the action of this viral product, ORF3b.”
 
While the SARS-CoV infection causes acute and severe pneumonia, SARS-CoV-2 infection may be asymptomatic or result in flu-like symptoms such as fever, cough and fatigue.
 < br /> Furthermore when comparing to SARS-CoV and influenza A virus infections, a hallmark of SARS-CoV-2 infection, COVID-19, is the poor induction of a type I interferon (IFN). Notably, impaired IFN responses are associated with the severity of COVID-19.
 
To date however, the molecular mechanisms underlying the inefficient IFN responses in SARS-CoV-2 infection remain unclear.
 
The study team by comparing the sequences of SARS-CoV-2-encoding genes to those of SARS-CoV, found that the gene length of SARS-CoV-2 ORF3b is markedly shorter than that of SARS-CoV ORF3b.
 
Since ORF3b of SARS-CoV is known as a viral antagonist against IFN production, the study team hypothesized that the difference on the length of ORF3b gene between SARS-CoV-2 and SARS-CoV may alter their anti-IFN activity and further may explain the difference in the symptoms of these two viral infections.
 
Interestingly the SARS-CoV-2 ORF3b is a more potent IFN antagonist than SARS-CoV ORF3b. Phylogenetic analyses and functional assays revealed that SARS-CoV-2-related viruses from bats and pangolins also encode shorter ORF3b gene products with strong anti-IFN activity.
 
Additional detailed analyses of approximately 17,000 SARS-CoV-2 sequences identified a natural variant, in which a longer ORF3b reading frame was reconstituted. This variant suppresses IFN even more efficiently than ORF3b of the parental SARS-CoV-2 strain.
 
Significantly in agreement with an association of IFN suppression with disease severity, the two patients in Ecuador harboring SARS-CoV-2 with the extended ORF3b variant were critically ill; one was treated in an intensive care unit and the other one died of COVID-19.
 
However, there is no direct evidence indicating that the viruses detected in these two COVID-19 patients in Ecuador are more pathogenic than the reference strain. Although they cannot tell whether this variant is associated with a different outcome in disease, it is plausible that naturally occurring length variants of ORF3b can potentially contribute to the emergence of more pathogenic SARS-CoV-2 variants.


One of the features distinguishing SARS-CoV-2 from its more pathogenic counterpart SARS-CoV is the presence of premature stop codons in its ORF3b gene. Here, we show that SARS-CoV-2 ORF3b is a potent interferon antagonist, suppressing the induction of type I interferon more efficiently than its SARS-CoV ortholog. Phylogenetic analyses and functional assays reveal that SARS-CoV-2-related viruses from bats and pangolins also encode truncated ORF3b gene products with strong anti-interferon activity. Furthermore, analyses of approximately 17,000 SARS-CoV-2 sequences identify a natural variant in which a longer ORF3b reading frame was reconstituted. This variant was isolated from two patients with severe disease and further increased the ability of ORF3b to suppress interferon induction. Thus, our findings not only help to explain the poor interferon response in COVID-19 patients but also describe the emergence of natural SARS-CoV-2 quasispecies with an extended ORF3b gene that may potentially affect COVID-19 pathogenesis. Credit: ©Kei Sato

Hence it will be critical to continue monitoring viral sequences to see whether novel ORF3b variants emerge during the current pandemic.
 
Dr Kei Sato commented "To our knowledge, this study is the first investigation revealing the role of a SARS-CoV-2-encoded protein that can be associated with the progression of COVID-19".
 
Thailand Medical News will be covering more on this new identified variant strains in the coming days.
 
For more on Coronavirus News, keep on logging to Thailand Medical News
 
 

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