SARS-CoV-2 rapidly evolves lineage-specific phenotypic differences when passaged repeatedly in immune-naïve mice.

Area of Science:

• Virology
• Evolutionary Biology
• Immunology

Background:

• SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) persistence challenges vaccine and treatment efficacy.
• Viral evolution is a key factor in reduced effectiveness of current medical countermeasures.
• Previous studies show serial infections can adapt viruses to new hosts.

Purpose of the Study:

• To investigate if passaging SARS-CoV-2 lineages (Beta and Delta) in K18-ACE2 mice drives human health-relevant evolution.
• To determine if viral evolution is dependent on the specific lineage.
• To identify specific mutations and their phenotypic consequences.

Main Methods:

• Serial passaging of unmodified B.1.351 (Beta) and B.1.617.2 (Delta) SARS-CoV-2 strains in K18-ACE2 mice over 20 passages.
• Infection of mice in a BSL-3 laboratory setting without imposed selective pressures.
• Analysis of disease severity at organism and lung tissue levels.
• Nanopore sequencing to identify mutations, including spike protein changes.
• Assessment of antibody resistance and interferon suppression.

Main Results:

• Late-passage viruses exhibited increased infectivity and mortality compared to early-passage strains.
• Late-passage Delta demonstrated significant antibody resistance and interferon suppression.
• A de novo spike S371F mutation was identified and linked to antibody resistance and interferon suppression.
• The S371F mutation, characteristic of Omicron, was sometimes co-inherited with E1182G.
• Both S371F and E1182G mutations are associated with mammalian GOLGA7 and ZDHHC5 interactions, influencing viral entry and host response.

Conclusions:

• SARS-CoV-2 exhibits a propensity for evolution with significant phenotypic consequences.
• Viral evolution patterns and outcomes vary depending on the specific lineage.
• The study suggests the contribution of non-dominant quasi-species in viral evolution.
• The identified mutations and their associated pathways offer insights into viral adaptation and potential therapeutic targets.