# New mouse model for inducible hACE2 expression enables to dissect SARS-CoV-2 pathology beyond the respiratory system

## TL;DR

A new mouse model expressing human ACE2 in multiple organs helps study SARS-CoV-2 effects beyond the lungs, revealing sex differences and neurological spread.

## Contribution

A novel inducible mouse model enables multisystemic study of SARS-CoV-2 infection and reveals sex-dependent disease outcomes.

## Key findings

- Male mice showed more severe disease outcomes, including weight loss, lung damage, and higher mortality compared to females.
- Intranasal infection led to viral spread to the brain and greater innate immune activation than intratracheal infection.
- The model supports preclinical evaluation of antiviral therapies and vaccines in a multisystemic context.

## Abstract

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection is not limited to the respiratory tract as receptors, including the angiotensin-converting enzyme 2 (ACE2), are expressed across many tissues. This study employed a new conditional mouse model, Rosa26creERT2/chACE2, which expresses human ACE2 (hACE2) across multiple organs, to investigate the effects of SARS-CoV-2 infection beyond the respiratory system. This strain demonstrated susceptibility to SARS-CoV-2 infection in a dose and sex-dependent manner, showing that infected male mice exhibited more severe disease outcomes, including significant weight loss, pronounced lung pathology and dysfunction, and increased mortality, compared to females. In contrast to intratracheal infection, intranasal virus administration facilitated viral spread to the brain, thereby underscoring the nasal route’s role in the pathogenesis of neurological manifestations. Intranasal infection also led to increased innate immune system activation as compared to intratracheal virus administration, even though both routes activated the adaptive immune response. This model provides a valuable tool to study SARS-CoV-2 in individual tissues or use a multisystemic approach, and it also advances possibilities for preclinical evaluation of antiviral therapies and vaccine strategies.

The online version contains supplementary material available at 10.1007/s00335-025-10115-1.