SARS-CoV-2 Variant-Specific Infectivity and Immune Profiles Are Detectable in a Humanized Lung Mouse Model.

Area of Science:

• Virology
• Immunology
• Animal Models

Background:

• Accurate small animal models are crucial for studying SARS-CoV-2 variant pathogenesis.
• Existing models may not fully recapitulate human immune responses or lung tissue interactions.

Purpose of the Study:

• To develop and validate a novel humanized mouse model (TKO-BLT-Lung mice) for SARS-CoV-2 variant research.
• To compare the infectivity and immunopathogenesis of different SARS-CoV-2 variants within this model.

Main Methods:

• Modification of a human immune system mouse model by implanting human lung tissue to create TKO-BLT-Lung (L) mice.
• Infection of these mice with SARS-CoV-2 variants (B.1.1.7 and an early B lineage 614D virus).
• Analysis of viral loads, immune profiles (Th1/Th2), and observed lesions in lung organoids.

Main Results:

• TKO-BLT-L mice supported SARS-CoV-2 replication, showing higher infectivity and viral loads for the B.1.1.7 variant compared to the 614D virus.
• Distinct immune profiles were observed, with a greater Th1 response to VIDO-01 and a greater Th2 response to B.1.1.7.
• Viral lesions were present in lung organoids, but no variant-specific differences were detected.

Conclusions:

• The TKO-BLT-L mouse model effectively supports SARS-CoV-2 infection and recapitulates key aspects of variant infectivity and pathogenesis.
• This model reveals previously unreported differences in immune responses between SARS-CoV-2 variants.
• The TKO-BLT-L model is a valuable tool for studying the immunopathobiology of emerging SARS-CoV-2 variants in a humanized lung context.