A Lung-Immune Dual-Humanized Mouse Using Cryopreserved Tissue Enables Infection and Immune Profiling of Human Common Cold Coronaviruses.

Summary

This study establishes a lung-immune dual-humanized mouse model using cryopreserved human fetal lung tissue, enabling robust infection by 229E, NL63, OC43, and HKU1. The platform validates Paxlovid efficacy against HKU1, reveals distinct phenotypes of human immune cells in implants versus native lungs, and demonstrates virus-specific T-cell responses and SARS-CoV-2 cross-reactivity after HKU1 infection.

Key Findings

• Optimized transplantation of cryopreserved human fetal lung tissue improved engraftment and supported robust infection by 229E, NL63, OC43, and HKU1.
• Validated therapeutic efficacy of Paxlovid against HKU1 in the dual-humanized model.
• Identified phenotypic differences of human immune cells between native mouse lungs and human lung implants in dual-humanized mice.
• Demonstrated virus-specific T-cell responses and SARS-CoV-2 cross-reactivity after HKU1 infection.

Clinical Implications

While preclinical, this model enables realistic testing of antivirals and vaccination strategies for human-tropic respiratory coronaviruses and helps anticipate cross-protection patterns relevant to clinical vaccine design.

Limitations

• Preclinical mouse model may not fully recapitulate human lung architecture and long-term immune dynamics.
• Reliance on fetal human tissues and specific engraftment conditions may limit generalizability across labs.

Future Directions

Leverage the platform to test pan-coronavirus vaccines, broaden antiviral validation, and dissect age- and comorbidity-related immune interactions across respiratory viruses.