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Chronological brain lesions after SARS-CoV-2 infection in hACE2-transgenic mice
Enric Vidal1, Carlos López-Figueroa1, Jordi Rodon1
1IRTA, Centre de Recerca en Sanitat Animal (CReSA, IRTA-UAB), Campus UAB, Bellaterra, Barcelona, Catalonia, Spain.
Abstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes respiratory disease, but it can also affect other organs including the central nervous system. Several animal models have been developed to address different key questions related to Coronavirus Disease 2019 (COVID-19). Wild-type mice are minimally susceptible to certain SARS-CoV-2 lineages (beta and gamma variants), whereas hACE2-transgenic mice succumb to SARS-CoV-2 and develop a fatal neurological disease. In this article, we aimed to chronologically characterize SARS-CoV-2 neuroinvasion and neuropathology. Necropsies were performed at different time points, and the brain and olfactory mucosa were processed for histopathological analysis. SARS-CoV-2 virological assays including immunohistochemistry were performed along with a panel of antibodies to assess neuroinflammation. At 6 to 7 days post inoculation (dpi), brain lesions were characterized by nonsuppurative meningoencephalitis and diffuse astrogliosis and microgliosis. Vasculitis and thrombosis were also present and associated with occasional microhemorrhages and spongiosis. Moreover, there was vacuolar degeneration of virus-infected neurons. At 2 dpi, SARS-CoV-2 immunolabeling was only found in the olfactory mucosa, but at 4 dpi intraneuronal virus immunolabeling had already reached most of the brain areas. Maximal distribution of the virus was observed throughout the brain at 6 to 7 dpi except for the cerebellum, which was mostly spared. Our results suggest an early entry of the virus through the olfactory mucosa and a rapid interneuronal spread of the virus leading to acute encephalitis and neuronal damage in this mouse model.
Insights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly invades the brain via the olfactory mucosa in hACE2-transgenic mice, causing acute encephalitis and neuronal damage within days.
Area of Science:
- Neuroscience
- Virology
- Pathology
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect the central nervous system.
- hACE2-transgenic mice are susceptible to SARS-CoV-2 and develop neurological disease, unlike wild-type mice.
- Understanding SARS-CoV-2 neuroinvasion and neuropathology is crucial for managing Coronavirus Disease 2019 (COVID-19).
Purpose of the Study:
- To chronologically characterize the neuroinvasion and neuropathology of SARS-CoV-2 in a susceptible mouse model.
- To investigate the temporal dynamics of viral spread within the central nervous system.
- To assess the inflammatory and degenerative changes associated with SARS-CoV-2 infection in the brain.
Main Methods:
- hACE2-transgenic mice were inoculated with SARS-CoV-2.
- Necropsies were performed at various time points post-inoculation (dpi).
- Histopathological analysis of brain and olfactory mucosa, SARS-CoV-2 virological assays (immunohistochemistry), and neuroinflammation marker assessment were conducted.
Main Results:
- SARS-CoV-2 was detected in the olfactory mucosa at 2 dpi and rapidly spread to most brain areas by 4 dpi.
- By 6-7 dpi, widespread brain lesions including nonsuppurative meningoencephalitis, astrogliosis, microgliosis, vasculitis, and neuronal vacuolar degeneration were observed.
- The cerebellum was largely spared, while other brain regions showed maximal viral distribution.
Conclusions:
- SARS-CoV-2 enters the brain early, likely through the olfactory mucosa.
- Rapid interneuronal spread leads to acute encephalitis and neuronal damage in this model.
- The findings highlight the potential for severe neurological complications in SARS-CoV-2 infections.
