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COVID-19 News - SARS-CoV-2 Nsp1 & Nsp15 Inhibits Stress Granule Formation  Dec 22, 2022  5 months ago
COVID-19 News: Scientists Discover Yet An Additional Mechanism By Which SARS-CoV-2 Disarms Host Immune Responses, NSP Inhibits Stress Granule Formation
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COVID-19 News: Scientists Discover Yet An Additional Mechanism By Which SARS-CoV-2 Disarms Host Immune Responses, NSP Inhibits Stress Granule Formation
COVID-19 News - SARS-CoV-2 Nsp1 & Nsp15 Inhibits Stress Granule Formation  Dec 22, 2022  5 months ago
COVID-19 News: Off late, there has been much heated discussions online about the fallacy of ‘immunity debt’ and many so called ‘experts’ denying the fact that SAR-CoV-2 infections causes the human immune system to become dysfunctional and worse, even with some contracting what is now known as COVID-19 immunodeficiency despite so many peer-reviewed studies showing the many mechanisms by which the SARS-CoV-2 virus is able to do so.!-sars-cov-2-destroying-children-s-robust-innate-system-is-the-

Numerous COVID-19 News coverages have already detailed how this SARS-CoV-2 infection caused immune dysfunction or COVID-19 induced immunodeficiency is paving the way for secondary opportunistic infections and  also the changing global immune landscape is also catalyzing the evolution of other pathogens.
Now, scientist from Dalhousie University-Canada and the University of Calgary- Canada have discovered yet another additional mechanism by which the SARS-CoV-2 virus is able to disarm the host immune responses, this time by using its non-structural protein (NSP) to inhibit stress granule formation, in the process causing the immune system to become dysfunctional.
Stress granules (SG) are typically dense aggregations in the cytosol composed of proteins and RNAs that appear when the cell is under stress.
The formation of stress granules is yet another way by which the host immune system detects viral infections and triggers defense programs to suppress viral replication and spread.
Stress granules are aggregates of RNA and proteins that serve an antiviral function by sequestering viral components and cellular factors needed by the invading virus to replicate.
As a result of this threat, various viruses have evolved specific mechanisms that prevent stress granule formation. Understanding these mechanisms can reveal potential targets for therapies that would disable viral inhibition of stress granules and render cells resistant to infection.
Several proteins from different coronaviruses have been shown to suppress SG formation upon overexpression, but there are only a handful of studies analyzing SG formation in coronavirus-infected cells.
In order to better understand SG inhibition by coronaviruses, the study team analyzed SG formation during infection with the human common cold coronavirus OC43 (HCoV-OC43) and the pandemic SARS-CoV2.
The researchers did not observe SG induction in infected cells and both viruses inhibited eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and SG formation induced by exogenous stress.
In SARS-CoV2 infected cells, the study team observed a sharp decrease in the levels of SG-nucleating protein G3BP1. Ectopic overexpression of nucleocapsid (N) and no n-structural proteins (Nsp) from both HCoV-OC43 and SARS-CoV2 inhibited SG formation.
Interestingly, the Nsp proteins of both viruses inhibited arsenite-induced eIF2α phosphorylation, and the Nsp1 of SARS-CoV2 alone was sufficient to cause a decrease in G3BP1 levels.
This phenotype was dependent on the depletion of cytoplasmic mRNA mediated by Nsp1 and associated with nuclear accumulation of the SG-nucleating protein TIAR.
In order to test the role of G3BP1 in coronavirus replication, the study team infected cells overexpressing EGFP-tagged G3BP1 with HCoV-OC43 and observed a significant decrease in virus replication compared to control cells expressing EGFP. The antiviral role of G3BP1 and the existence of multiple SG suppression mechanisms that are conserved between HCoV-OC43 and SARS-CoV2 suggest that SG formation may represent an important antiviral host defense that coronaviruses target to ensure efficient replication.
Because both OC43 and SARS-CoV2 each dedicate more than one gene product to inhibit stress granule formation, the study findings suggests that viral disarming of stress granule responses is central for productive infection.
The study finings that of all the viral proteins involved in this inhibiting of stress granule formation, the Nsp1 and Nsp15 proteins are the key proteins that play a critical role.
Th study findings were published in the peer reviewed journal: PLOS Pathogens.
According to the study team, in the last 10 years, zoonotic betacoronaviruses such as Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2 have been responsible for a staggering number of infections and deaths.
Interestingly, some coronavirus proteins, such as the SARS-CoV-2 nucleocapsid protein, have shown the ability to inhibit stress granule formation during ectopic overexpression.
The study team stressed that understanding how viruses like SARS-CoV-2 inhibit the formation of stress granules could provide therapeutic targets to improve cellular resistance to infections.
For the research, the study team infected human embryonic kidney (HEK) 293A cells with HCoV-OC43. The researchers used immunofluorescence staining for T-cell internal antigen-related protein (TIAR) to detect the presence of stress granules in the infected cells at multiple time points post-infection.
In order to analyze the active inhibition of stress granule formation by HCoV-OC43, the study team also used sodium arsenite to induce stress granule formation and eukaryotic translation initiation factor 2α (eIF2α) phosphorylation in mock and virus-infected HEK 293A cells.
The same series of analyses were repeated in human colon adenocarcinoma (HCT-8) cells to determine if the inhibition of stress granule formation by HCoV-OC43 was specific for HEK 293A cells.
The ability of HCoV-OC43 to inhibit the eIF2α phosphorylation-independent stress granule formation was also examined using Silvesterol, which initiates stress granule formation without inducing eIF2α phosphorylation.

The analyses were repeated using immunofluorescence staining with other stress granule markers such as Ras-guanosine triphosphate (GTP)ase-activating protein SH3-domain-binding proteins 1 and 2 (G3BP1 and G3BP2), and T-cell internal antigen 1 (TIA-1), as well as eukaryotic translation initiation factors 4 subunit G and 3 subunit B (eIF4G and eIF3B), to determine whether the inhibition of stress granule formation by HCoV-OC43 was limited to stress granules containing TIAR.
In order, to determine the inhibition of stress granule formation by SARS-CoV-2, HEK 293A cells expressing angiotensin-converting enzyme-2 (ACE-2) were infected with SARS-CoV-2. TIAR levels in SARS-CoV-2 infected cells and mock-infected cells were compared, and reverse transcription polymerase chain reaction (RT-PCR) was used to determine the levels of G3BP1 and TIAR messenger RNA in the infected cells.
Enhanced green fluorescent protein (EGFP)-tagged nucleocapsid protein and nonstructural protein 15 (Nsp15) of HCoV-OC43 and SARS-CoV-2 were overexpressed in HEK 293A cells to determine their role in the inhibition of stress granule formation. The role of Nsp15 in the depletion of G3BP1 mRNA and protein was also examined.
The study findings showed no stress granule formation in cells infected with HCoV-OC43 and SARS-CoV-2. Both coronaviruses also inhibited eIF2α phosphorylation and stress granule formation from exogenous stress.
It was found that nucleocapsid protein and Nsp15 from HCoV-OC43 and SARS-CoV-2 inhibited stress granule formation when overexpressed ectopically.
Importantly, the Nsp15 protein from HCoV-OC43 and SARS-CoV-2 also inhibited the eIF2α phosphorylation induced by sodium arsenite.
It was also found that in cells infected with SARS-CoV-2, the levels of G3BP1 protein decreased sharply, and the nuclear accumulation of TIAR was observed. When cells overexpressing G3BP1 were infected with HCoV-OC43 and compared to HCoV-OC43-infected cells without G3BP1 overexpression, significantly lower levels of viral replication were observed in the cells with overexpressed G3BP1, indicating that G3BP1 played an important antiviral role.

Although cells overexpressing G3BP1 exhibited significantly high levels of stress granule formation, a considerable number of cells infected with HCoV-OC43 also showed inhibition of stress granule formation, indicating the presence of multiple translational arrest interference mechanisms by HCoV-OC43 and SARS-CoV-2 that inhibit stress granule formation.
The study is the first to investigate the inhibition of stress granule formation by two coronaviruses ie SARS-CoV-2 and the human cold coronavirus OC43. The study also examined the role of nucleocapsid protein, and non-structural proteins Nsp1 and Nsp15 in inhibiting stress granule formation. Additionally, the antiviral role of the G3BP1 protein was also investigated.
The study findings indicated that nucleocapsid protein, NSp1 and Nsp15 of the two viruses inhibit stress granule formation and enable viral replication through separate but complementary processes.
The study findings show that the inactivation of stress granule formation is essential for viral replication and infection, and the mechanisms through which these viruses inhibit stress granule formation could be potential therapeutic targets.
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