Omicron subvariant BA.5 efficiently infects lung cells

Area of Science:

• Virology
• Molecular Biology
• Infectious Diseases

Background:

• SARS-CoV-2 Omicron subvariants BA.1 and BA.2 showed reduced lung cell infection compared to earlier variants, correlating with lower pathogenicity.
• The infectivity and pathogenicity of the BA.5 subvariant, which succeeded BA.1 and BA.2, remained unclear regarding lung cell infection.

Purpose of the Study:

• To investigate whether the SARS-CoV-2 Omicron BA.5 subvariant retains the attenuated lung cell infection phenotype observed in BA.1 and BA.2.
• To determine the molecular mechanisms underlying BA.5's lung cell entry and replication efficiency.

Main Methods:

• Comparative analysis of spike (S) protein cleavage at the S1/S2 site for BA.5 versus BA.1 and BA.2.
• Assessment of cell-cell fusion and lung cell entry efficiency mediated by BA.5 S protein.
• Evaluation of BA.5 replication in cultured human lung cells.
• In vivo studies of BA.5 replication in the lungs of female Balb/c mice and the nasal cavity of female ferrets.

Main Results:

• The BA.5 spike protein demonstrated increased S1/S2 site cleavage and enhanced efficiency in driving cell-cell fusion and lung cell entry compared to BA.1 and BA.2.
• The H69Δ/V70Δ mutation was identified as crucial for the increased lung cell entry observed in BA.5.
• BA.5 exhibited efficient replication in cultured lung cells and showed significantly higher replication in the lungs of mice and ferrets compared to BA.1.

Conclusions:

• The SARS-CoV-2 Omicron BA.5 subvariant has regained the capacity for efficient lung cell infection, a key factor for severe disease.
• The evolution of Omicron subvariants can lead to a partial reversal of attenuation, with BA.5 demonstrating increased pathogenicity potential.
• Findings highlight the dynamic nature of viral evolution and the potential for increased virulence in emerging SARS-CoV-2 strains.