Redirecting the JAK-STAT signal blocks the SARS-CoV-2 replication.

Area of Science:

• Immunology
• Virology
• Biotechnology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection impairs type I interferon (IFN) signaling, leading to severe lung damage.
• Cytokine modifications for improved pharmacological properties can sometimes reduce antiviral activity.

Purpose of the Study:

• To engineer an enhanced form of interferon-beta (IFN-β) with improved biological activity against SARS-CoV-2.
• To investigate the mechanism by which the engineered IFN-β derivative impacts viral infection and host immune response.

Main Methods:

• Genetic code expansion was used to engineer IFN-β with 3-amino tyrosine (IFN-β-A).
• The study assessed STAT2 expression reactivation in virus-infected human cells.
• JAK/STAT cell signaling pathways were analyzed to understand the mechanism of action.

Main Results:

• Engineered IFN-β-A reactivated STAT2 expression in SARS-CoV-2 infected human cells.
• The modified cytokine triggered JAK-STAT cell signaling without altering signal activation or serum half-life.
• IFN-β-A demonstrated potential to stabilize protein-receptor complexes.

Conclusions:

• Genetically encoded IFN-β-A is a promising therapeutic candidate for controlling SARS-CoV-2 infection.
• The engineered cytokine offers a potential strategy to overcome IFN pathway impairment during viral infections.