‘Silent killer’: it turns out that COVID-19 causes inflammation in the brain

‘Silent killer’: it turns out that COVID-19 causes inflammation in the brain

‘Silent killer’: it turns out that COVID-19 causes inflammation in the brain

Abstract: COVID-19 infection activates the same inflammatory response in the brain as Parkinson’s disease, a new study reports.

Source: University of Queensland

Research led by the University of Queensland has shown that COVID-19 activates the same inflammatory response in the brain as Parkinson’s disease.

The discovery identified a potential future risk for neurodegenerative conditions in people who have had COVID-19, as well as a possible treatment.

The UQ team was led by Professor Trent Woodruff and Dr Eduardo Albornoz Balmaceda from UQ’s School of Biomedical Sciences and virologists from the School of Chemistry and Molecular Biosciences.

“We studied the effect of the virus on the brain’s immune cells, ‘microglia’, which are key cells involved in the progression of brain diseases such as Parkinson’s and Alzheimer’s,” Professor Woodruff said.

“Our team grew human microglia in the laboratory and infected the cells with SARS-CoV-2, the virus that causes COVID-19.

“We found that the cells actually became ‘angry’, activating the same pathway that Parkinson’s and Alzheimer’s proteins can activate in the disease, the inflammasome.”

dr. Albornoz Balmaceda said that the activation of the inflammasome pathway caused a “fire” in the brain, which begins a chronic and long-term process of killing neurons.

“It’s kind of a silent killer, because you don’t see any outward symptoms for years,” said Dr. Albornoz Balmaceda.

“This may explain why some people who have had COVID-19 are more susceptible to developing Parkinson’s-like neurological symptoms.”

The researchers found that a spike in the virus’s protein was enough to start the process, and that it was further exacerbated when proteins associated with Parkinson’s disease were already present in the brain.

“So if someone already has a predisposition to Parkinson’s disease, having COVID-19 could be like adding more fuel to that ‘fire’ in the brain,” Professor Woodruff said.

“The same would be true for the predisposition to Alzheimer’s disease and other dementias that are associated with inflammation.”

‘Silent killer’: it turns out that COVID-19 causes inflammation in the brain
The discovery identified a potential future risk for neurodegenerative conditions in people who have had COVID-19, as well as a possible treatment. The image is in the public domain

But the study also found a potential treatment.

The researchers used a class of inhibitory drugs developed by UQ that are currently in clinical trials with Parkinson’s patients.

“We found that it successfully blocked the inflammatory pathway that activated COVID-19, essentially putting out the fire,” said Dr. Albornoz Balmaceda.

“The drug reduced inflammation in both mice infected with COVID-19 and in human microglia cells, suggesting a possible treatment approach to prevent neurodegeneration in the future.”

Professor Woodruff said that while the similarity between the impact of COVID-19 and the disease dementia on the brain is worrying, it also means that a possible treatment already exists.

“Further research is needed, but this is a potentially novel approach to treating a virus that could otherwise have untold long-term health consequences.”

The research was jointly led by Dr Alberto Amarilla Ortiz and Associate Professor Daniel Watterson, and included 33 co-authors from UQ and abroad.

About this news about research on the disease COVID-19 and neuroinflammation

Author: Press office
Source: University of Queensland
Contact: Press Office – University of Queensland
Picture: The image is in the public domain

See also

This shows a man holding his stomach

Original research: Open access.
SARS-CoV-2 triggers NLRP3 inflammasome activation in human microglia via the spike protein” by Eduardo A. Albornoz et al. Molecular psychiatry


Abstract

SARS-CoV-2 triggers NLRP3 inflammasome activation in human microglia via the spike protein

Coronavirus disease-2019 (COVID-19) is primarily a respiratory illness, however, a growing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases of possible Parkinson’s disease.

Since microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, we investigated here whether SARS-CoV-2 can induce microglial NLRP3 inflammasome activation.

Using SARS-CoV-2 infection of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as a preclinical model for COVID-19, we established the presence of the virus in the brain along with microglia activation and upregulation of the NLRP3 inflammasome compared to uninfected mice.

Next, using a human monocyte-derived microglia model, we identified that SARS-CoV-2 isolates can bind to and enter human microglia in the absence of viral replication.

This virus-microglia interaction directly induced strong inflammasome activation, even in the absence of another priming signal. Mechanistically, we showed that the purified SARS-CoV-2 spike glycoprotein activated the NLRP3 inflammasome in microglia with LPS, in an ACE2-dependent manner.

Spike protein can also trigger the inflammasome in microglia via NF-κB signaling, allowing activation by ATP, nigericin, or α-synuclein. Namely, activation of microglial inflammasomes mediated by SARS-CoV-2 and spike protein was significantly enhanced in the presence of α-synuclein fibrils and was completely removed by inhibition of NLRP3.

Finally, we show that SARS-CoV-2-infected hACE2 mice treated orally after infection with the NLRP3 inhibitor drug MCC950 significantly reduced microglial inflammasome activation and increased survival compared to untreated SARS-CoV-2-infected mice.

These results support a possible mechanism of microglial innate immune activation of SARS-CoV-2, which could explain the increased vulnerability to the development of neurological symptoms similar to Parkinson’s disease in individuals infected with COVID-19, and a potential therapeutic avenue for intervention.

title_words_as_hashtags]

Leave a Comment

Your email address will not be published. Required fields are marked *