Pulmonary SARS-CoV-2 infection leads to para-infectious immune activation in the brain
Cordelia Dunai1,2, Claire Hetherington2, Sarah A Boardman2
1NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Liverpool, United Kingdom.
Abstract:
Neurological complications, including encephalopathy and stroke, occur in a significant proportion of COVID-19 cases but viral protein is seldom detected in the brain parenchyma. To model this situation, we developed a novel low-inoculum K18-hACE2 mouse model of SARS-CoV-2 infection during which active viral replication was consistently seen in mouse lungs but not in the brain. We found that several mediators previously associated with encephalopathy in clinical samples were upregulated in the lung, including CCL2, and IL-6. In addition, several inflammatory mediations, including CCL4, IFNγ, IL-17A, were upregulated in the brain, associated with microglial reactivity. Parallel in vitro experiments demonstrated that the filtered supernatant from SARS-CoV-2 virion exposed brain endothelial cells induced activation of uninfected microglia. This model successfully recreates SARS-CoV-2 virus-associated para-infectious brain inflammation which can be used to study the pathophysiology of the neurological complications and the identification of potential immune targets for treatment.
Insights
COVID-19 neurological complications may stem from lung inflammation, not direct brain infection. This study introduces a mouse model showing lung inflammation mediators can trigger brain inflammation and microglial activation, offering new therapeutic targets.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- Neurological complications like encephalopathy and stroke are common in COVID-19.
- Viral proteins are rarely found in the brain during SARS-CoV-2 infection.
- The mechanisms behind COVID-19-associated neurological issues remain unclear.
Purpose of the Study:
- To develop a mouse model that mimics SARS-CoV-2-associated para-infectious brain inflammation.
- To investigate the link between lung inflammation and brain immune responses in COVID-19.
- To identify potential immune targets for treating neurological complications.
Main Methods:
- Established a low-inoculum K18-hACE2 mouse model of SARS-CoV-2 infection.
- Analyzed viral replication in lungs and brain tissue.
- Measured levels of inflammatory mediators (cytokines and chemokines) in lung and brain.
- Conducted in vitro experiments using brain endothelial cells and microglia.
Main Results:
- Active SARS-CoV-2 replication was confined to the lungs, not the brain.
- Lung inflammation mediators (CCL2, IL-6) were upregulated.
- Brain inflammation mediators (CCL4, IFNγ, IL-17A) and microglial reactivity were observed.
- Supernatant from infected brain endothelial cells activated uninfected microglia in vitro.
Conclusions:
- The developed mouse model effectively replicates SARS-CoV-2-associated para-infectious brain inflammation.
- Lung-derived inflammatory mediators may drive brain inflammation and microglial activation.
- This model is valuable for studying COVID-19 neurological pathophysiology and identifying immune targets.
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