IFITM3 deficiency drives SARS-CoV-2 adaptation while preserving variant-specific traits

Area of Science:

• Virology
• Immunology
• Genetics

Background:

• SARS-CoV-2 demonstrates broad host tropism, but determinants of interspecies adaptation are unclear.
• Interferon-induced transmembrane protein 3 (IFITM3) is a crucial antiviral factor, with genetic variations affecting its function in human populations.

Purpose of the Study:

• To investigate the role of IFITM3 in the interspecies adaptation of SARS-CoV-2.
• To determine how IFITM3 deficiency impacts viral replication, pathogenesis, and mutation accumulation in a new host.

Main Methods:

• Passaging SARS-CoV-2 variants (Beta and Omicron BA.4) in IFITM3-deficient versus wild-type mice.
• Analyzing viral replication, pathogenesis markers, and genomic sequences in infected mice.
• Evaluating host gene expression related to lung function and inflammation.

Main Results:

• IFITM3-deficient mice showed enhanced SARS-CoV-2 replication and pathogenesis compared to wild-type mice.
• Viral adaptation in IFITM3-deficient hosts was associated with specific amino acid substitutions, indicating limited mutation accumulation.
• SARS-CoV-2 Beta variant caused lung dysfunction, while Omicron BA.4 exhibited nasal tropism with reduced lung involvement and inflammation.

Conclusions:

• IFITM3 deficiency accelerates SARS-CoV-2 adaptation to new hosts, enhancing viral fitness.
• Host adaptation preserves intrinsic variant-specific characteristics, influencing disease presentation.
• Mouse-adapted SARS-CoV-2 models facilitate comparative studies of viral variants and host-pathogen interactions.