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Source: COVID-19 News  Apr 03, 2021  13 days ago
COVID-19 News: Oxford Study Shows That SARS-CoV-2 Coronavirus Inhibits Host Cellular Response To Interferon!
COVID-19 News: Oxford Study Shows That SARS-CoV-2 Coronavirus Inhibits Host Cellular Response To Interferon!
Source: COVID-19 News  Apr 03, 2021  13 days ago
COVID-19 News: A new study by researchers from Oxford University has found that the SARS-CoV-2 coronavirus inhibits the host cellular response to interferon.

The study found that human host cells respond to infection by SARS-CoV-2 coronavirus by producing cytokines including type I and III interferons (IFNs) and proinflammatory factors such as IL6 and TNF.
Typically interferons (IFNs) can limit SARS-CoV-2 replication but cytokine imbalance contributes to severe COVID-19.
The research team studied how cells detect SARS-CoV-2 infection. They team reported that the cytosolic RNA sensor MDA5 was required for type I and III interferons induction in the lung cancer cell line Calu-3 upon SARS-CoV-2 infection. Type I and III IFN induction further required MAVS and IRF3. In contrast, induction of IL6 and TNF was independent of the MDA5-MAVS-IRF3 axis in this setting.
The team further found that SARS-CoV-2 infection inhibited the ability of cells to respond to interferons (IFNs). In sum, we identified MDA5 as a cellular sensor for SARS-CoV-2 infection that induced type I and III IFNs.
The study findings were published on a preprint server and are currently being peer reviewed.
The COVID-19 disease is typically associated with the development of acute respiratory distress syndrome (ARDS), characterized by exacerbated inflammation in the lungs and significantly upregulated production of cytokines.
Interestingly the increased expression of genes associated with interferon production is often observed in those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, though serum levels are frequently unexpectedly low. Intranasal, though not intravenous, administration of type I interferon has also been shown to be beneficial to mice infected with SARS-CoV-2, suggesting that the way in which the cells of the airway and alveolar detect and respond to the virus by producing interferon may have been negatively impacted following infection.
It has been found that the early cellular response to viral challenge is largely mediated by proteins that detect foreign nucleic acid sequences in the cytosol. Retinoic acid-inducible gene-I-like receptors are a family of pattern recognition receptor proteins that have been implicated in the sensing of coronaviruses.
Importantly the two proteins within this family that detect specific types of RNA structure are: 1) retinoic acid-inducible 60 gene I (RIG-I) and 2) melanoma differentiation-associated protein 5 (MDA5). Once bound with viral RNA, these proteins trigger a signaling cascade that results in the production of cytokines such as interferon.
The study team explored the effect of SARS-CoV-2 infection on the function of RIG-I and MDA5, and ultimately on interferon production.
The study team screened several cell lines for their ability to host SARS-CoV-2 and detectably produce virus nucleocapsid RNA within 24 hours, finding that Calu-3, HEK293, and Huh7 cells, could host the virus, but only Calu-3 cells induced a detectable cytokine response. Calu-3 cells are sourced from human lung tissue and may therefore be better evolved to provide an immune response against coronaviruses.
Significantly, upregulation of type I and III interferons was observed upon infection, alongside other proinflammatory cytokines such as interleukin-6, and the major immune signaling pathways were activated, including RIG-I and MDA5.
In the study, short hairpin RNA (shRNA) - a synthetic molecule used to silence gene expression by RNA interference, was used to knockdown mitochondrial antiviral-signaling protein (MAVS), with which both RIG-I and MDA5 must interact following binding with viral RNA. Knockdown cells experienced a higher load of SARS-CoV-2 and exhibited depleted interferon levels, though the levels of mRNA coding for some other cytokines (interleukin-6 and tumor necrosis factor) were not altered.
It was noted that cells with knocked out MDA5 or interferon regulatory factor 3 (IRF3), which is activated downstream of MAVS, showed the lowest concentration of interferon coding mRNAs in response to SARS-CoV-2 infection, while also maintaining IL-6 and TNF levels. Knocking out RIG-I or stimulator of interferon genes (STING), a cystolic DNA sensor, had little influence on SARS-CoV-2 infection, suggesting that the cystolic GMP-AMP synthase-STING pathway is not involved in SARS-CoV-2 sensing.
The study team demonstrated that the RNA sensor MDA5 and its downstream partners MAVS and IRF3 are involved in the type I and III interferon response to SARS-CoV-2, while RIG-I is largely uninvolved, as has been supported by several other studies. However, the authors highlight several reports of opposing results, which include indications that RIG-I is involved in sensing additionally or in lieu of MDA5. A diverse range of other pattern recognition receptors are involved in the immune response and the reason for the observed variation is not yet entirely understood. The STING system, for example, has been shown to be activated following cell damage by other infections such as Dengue virus. Though the response to coronavirus is not yet known, it could become active at time points later than observed in this study.
The study team importantly noticed that infected cells demonstrated lowered MxA protein production compared with uninfected bystanders, a virus inhibitor expressed in response to interferon, IL-6, and other cytokines.
The study findings suggest that SARS-CoV-2 suppresses an upstream elicitor of this protein, indicated to be interferon, by encoding a viral protein that interferes with the system, as has been suggested by this and other work. Open reading frame 3a of SARS-Cov-1 is known to target and inhibit the interferon alpha/beta receptor, a widespread membrane receptor of type I interferon, and the group suggests that SARS-CoV-2 likely produces additional proteins that block interferon signaling.
The study team suggests that the SARS-CoV-2 viral infection antagonized IFN receptor signalling. Indeed, other studies identified proteins in the IFNAR signalling cascade as targets of specific SARS CoV-2 proteins. This includes the viral ORF6, which prevents STAT1 nuclear translocation and activation of ISG promoters.
Additionally, SARS-CoV-2 has been shown to downregulate  protein expression of IFNAR1, JAK1 and TYK2, which are all involved in IFN receptor signalling.
Like SARS-CoV-2, SARS-CoV encodes viral proteins that interfere with the type I IFN system. For example, ORF3a from SARS-CoV targets IFNAR directly, and NSP1 inhibits STAT1 phosphorylation and IFNAR signalling by supressing host gene expression.
Therefore, it is likely that SARS-CoV-2 has additional proteins that block IFN receptor signalling. Our work supports the idea that SARS-CoV-2 inhibits the response to type I IFNs, 220 likely reducing host immunity and increasing virus propagation
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