SARS-CoV-2 ORF8 modulates lung inflammation and clinical disease progression

Area of Science:

• Virology
• Immunology
• Pathogenesis

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the COVID-19 pandemic.
• SARS-CoV-2 has a large genome encoding structural, non-structural, and accessory proteins.
• Accessory proteins influence viral replication and pathogenesis, though not essential for disease.

Purpose of the Study:

• To investigate the role of SARS-CoV-2 accessory proteins in host inflammatory response and pathogenesis.
• To determine the specific function of the ORF8 accessory protein.

Main Methods:

• Synthesis of novel infectious SARS-CoV-2 clones lacking specific accessory proteins, including ORF8.
• Infection of mice with wild-type, ORF8-deficient, and mutant SARS-CoV-2 viruses.
• Analysis of host inflammatory response, including weight loss and macrophage infiltration in lungs.

Main Results:

• Mice infected with SARS-CoV-2 lacking ORF8 showed increased weight loss and exacerbated lung macrophage infiltration.
• Naturally occurring ORF8 mutations found in variants of concern influenced disease severity in mice.
• The absence or mutation of ORF8 significantly impacted viral pathogenesis.

Conclusions:

• The SARS-CoV-2 accessory protein ORF8 plays a critical role in modulating the host inflammatory response.
• ORF8 influences SARS-CoV-2 pathogenesis and disease severity.
• Naturally occurring mutations in ORF8 can alter the impact of the virus on host health.