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A Murine Model of Dengue Virus-induced Acute Viral Encephalitis-like Disease
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New mouse model for inducible hACE2 expression enables to dissect SARS-CoV-2 pathology beyond the respiratory system
Federica Gambini1, Dominik Arbon2, Petr Nickl2
1Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, Prague, 142 20, Czech Republic.
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.
Insights
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) can affect multiple organs, not just the lungs. A new mouse model reveals male mice experience more severe SARS-CoV-2 disease, and intranasal infection spreads the virus to the brain.
Area of Science:
- Virology
- Immunology
- Pathology
Background:
- Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) utilizes angiotensin-converting enzyme 2 (ACE2) receptors for cell entry.
- ACE2 receptors are expressed in various human tissues beyond the respiratory system, suggesting potential for multisystemic infection.
- Understanding SARS-CoV-2 pathogenesis in different organs is crucial for developing effective treatments and vaccines.
Purpose of the Study:
- To investigate the systemic effects of SARS-CoV-2 infection using a novel mouse model expressing human ACE2 (hACE2) across multiple organs.
- To determine the impact of infection route (intranasal vs. intratracheal) on viral spread and disease severity.
- To evaluate sex-specific differences in SARS-CoV-2 pathogenesis.
Main Methods:
- Development and utilization of a conditional mouse model (Rosa26creERT2/chACE2) expressing hACE2 in multiple tissues.
- Administration of SARS-CoV-2 via intranasal and intratracheal routes.
- Assessment of disease severity, including weight loss, lung pathology, mortality, and immune responses (innate and adaptive).
Main Results:
- The hACE2 mouse model is susceptible to SARS-CoV-2 in a dose- and sex-dependent manner.
- Male mice exhibited significantly more severe disease, including greater weight loss, lung damage, and higher mortality compared to female mice.
- Intranasal infection promoted viral spread to the brain and heightened innate immune activation compared to intratracheal infection, while both routes induced adaptive immunity.
Conclusions:
- The developed mouse model is a valuable tool for studying SARS-CoV-2's multisystemic effects and for preclinical evaluation of antiviral therapies and vaccines.
- SARS-CoV-2 infection can lead to severe neurological manifestations, particularly via the intranasal route.
- Sex differences play a significant role in SARS-CoV-2 disease severity, with males being more vulnerable.
