Washington University Study Shows That Surface Proteins On SARS-CoV-2 Virus Modifies Expression Of Key Cytokines And Chemokines In Cell Lines

A new study by researchers from Washington University School of Medicine- Saint Louis, Missouri has found that the surface proteins on sars-cov-2 virus modifies expression of key cytokines and chemokines in cell lines, inducing induce interferon-dependent inflammation.


 
According to the study team, SARS-CoV-2, the virus that has caused the COVID-19 pandemic, robustly activates the host immune system in critically ill patients. Understanding how the virus engages the immune system will facilitate the development of needed therapeutic strategies.
 
The study team demonstrates both in vitro and in vivo that the SARS-CoV-2 surface proteins Spike (S) and Envelope (E) activate the key immune signaling interferon (IFN) pathway in both immune and epithelial cells independent of viral infection and replication. These proteins induce reactive oxidative species generation and increases in human and murine specific IFN-responsive cytokines and chemokines, similar to their upregulation in critically ill COVID-19 patients. Induction of IFN signaling is dependent on canonical but discrepant inflammatory signaling mediators as the activation induced by S is dependent on IRF3, TBK1, and MYD88 while that of E is largely MYD88 independent. Furthermore, these viral surface proteins, specifically E, induced peribronchial inflammation and pulmonary vasculitis in a mouse model.
 
The study team shows that the organized inflammatory infiltrates are dependent on type I IFN signaling, specifically in lung epithelial cells. These findings underscore the role of SARS-CoV-2 surface proteins, particularly the understudied E protein, in driving cell specific inflammation and their potential for therapeutic intervention.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2020.12.14.422710v1
 
The COVID-19 disease manifests as a respiratory illness, which disproportionately affects the elderly population and people with comorbidities. Patients with severe COVID-19 developed respiratory failure caused by poor gas exchange and massive lung inflammation.
 
This coronavirus is genetically 79.5% similar to SARS-CoV-1 and 50% similar to the Middle East respiratory syndrome (MERS). The SARS-CoV-2 virus also used the same host receptor - angiotensin-converting enzyme 2 (ACE2) - as SARS-CoV-1 for entry into the host cell by binding its S protein to ACE2. The S protein binds ACE2 more strongly than SARS-CoV, though these 2 S proteins have similar tertiary structures.
 
It is known that the SARS-CoV-2 activates the immune system of the host and causes widespread inflammation in patients with severe COVID-19. Knowing how the virus engages with the host immune system will enable the development of much needed therapeutic strategies to fight COVID-19.
 
The study team demonstrated that the SARS-CoV-2 surface proteins alone triggered innate cell activity and the interferon signaling pathway.
 
The team showed that surface proteins spike (S) and envelope (E) of SARS-CoV-2 activate the key immune signaling interferon (IFN) pathway in both immune cells and epithelial cells independent of viral infection and replication both in vitro and in vivo.
 
The study team told Thailand g>Medical News that tt was found that these surface proteins trigger the generation of reactive oxidative species and elevation in human and murine specific IFN-responsive cytokines and chemokines, similar to what happens in severe COVID-19 patients. Induction of IFN signaling relies on established but discrepant inflammatory signaling mediators as the activation induced by the surface protein S is dependent on IRF3, TBK1, and MYD88, while that of the envelope protein E is largely MYD88 independent.
 
The study team showed that these viral antigens individually alter the expression of key chemokines and cytokines, including many regulated by IFN, in both human and murine cell lines.
 
More importantly it was found that these viral proteins, specifically the E protein, triggered peribronchial inflammation and pulmonary vasculitis in mouse models.
 
The study team also showed that the organized inflammatory infiltrates rely on type I IFN signaling, specifically in the case of lung epithelial cells. These findings highlight the crucial role of SARS-CoV-2 surface proteins, especially the less known and less studied E protein, in triggering cell-specific inflammation and their potential for therapeutic intervention.
 
It is known that the innate immune system of our body is our first line of defense critical for viral clearance while also playing a key role in the pathogenesis of many viral pathogens.
 
Numerous studies have shown that COVID-19 pathogenesis is characterized by a hyperinflammatory state and an uncontrolled immune response. Patients with severe COVID-19 experience a “cytokine storm” due to the release of high levels of proinflammatory mediators, and this strength of this storm is directly proportional to the viral load and severity of disease.
 
The study findings also highlight the importance of the direct effect of coronavirus surface proteins and will usher investigation of other viral surface proteins as determinants of the host-pathogen interaction.
 
The study findings showed that the viral antigens alone altered the expression of proinflammatory chemokines and cytokines, including the ones regulated by IFN, in both human and murine cell lines.
 
The study team believes that their research has significant implications for the virus-host immune response as they show that the activation of innate immune signaling pathways happen independently of viral nucleic acid detection. A better understanding of the immune response to viral surface proteins is important for decoding how this novel virus engages with the immune system of the host.
 
This research has broad implications for the pathogen-host immune response; we show that activation of innate immune signaling pathways independent of viral nucleic acid detection by pathogen recognition receptors engage host immunity similarly to complete infectious virus.
 
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