SARS-CoV-2 Disrupts Proximal Elements in the JAK-STAT Pathway.

Area of Science:

• Virology and Immunology
• Cellular Biology
• Molecular Mechanisms of Viral Infection

Background:

• SARS-CoV-2 infects multiple human organs, but the molecular mechanisms of viral replication in diverse cellular environments are not fully understood.
• Understanding how the virus interacts with host cells is crucial for developing effective antiviral strategies against COVID-19.

Purpose of the Study:

• To identify cellular proteins and pathways broadly affected by SARS-CoV-2 infection across different human cell types.
• To elucidate the molecular mechanisms by which SARS-CoV-2 evades the host innate immune response, specifically interferon signaling.

Main Methods:

• Generation of phenotypically diverse, SARS-CoV-2-infectible human cell lines from various organs.
• Longitudinal analysis of cellular proteins and pathways post-infection.
• Systematic investigation of the Janus kinase-STAT (JAK-STAT) pathway, including protein analysis and chemical inhibition studies.

Main Results:

• SARS-CoV-2 infection universally inhibited interferon signaling across all tested cell types.
• The virus targeted proximal JAK-STAT pathway components (JAK1, Tyk2, IFNAR1), leading to cellular desensitization to type I interferon.
• IFNAR1 underwent ubiquitination upon infection, and inhibition of JAK kinases enhanced viral infection in stem cell-derived cultures.

Conclusions:

• Suppression of interferon signaling is a key mechanism employed by SARS-CoV-2 to evade antiviral innate immunity.
• Targeting viral mediators of immune evasion could be a viable strategy to block SARS-CoV-2 replication in COVID-19 patients.
• These findings reveal how SARS-CoV-2 propagates in different tissues despite the host's immune response.