Summary: COVID-19 infection activates the same inflammatory response in the brain as Parkinson’s disease, a new study has found.
Source: University of Queensland
Research by the University of Queensland has found that COVID-19 activates the same inflammatory response in the brain as Parkinson’s disease.
The discovery identified a potential future risk of neurodegenerative diseases in people with COVID-19, but also 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 immune cells in the brain, the ‘microglia’ which are the key cells involved in the progression of brain diseases like Parkinson’s disease and Alzheimer’s disease,” said the professor. Woodruff.
“Our team grew human microglia in the lab and infected the cells with SARS-CoV-2, the virus that causes COVID-19.
“We found that the cells did indeed become ‘angry’, activating the same pathway that Parkinson’s and Alzheimer’s proteins can activate in disease, the inflammasomes.”
Dr Albornoz Balmaceda said triggering the inflammasome pathway ignited a “fire” in the brain, which begins a chronic and sustained process of neuron destruction.
“It’s kind of a silent killer, because you don’t see any outward symptoms for many years,” Dr. Albornoz Balmaceda said.
“This may explain why some people who have had COVID-19 are more vulnerable to developing neurological symptoms similar to Parkinson’s disease.”
The researchers found that the spike protein of the virus was enough to start the process and was further exacerbated when there were already proteins in the brain linked to Parkinson’s disease.
“So if someone is already predisposed to Parkinson’s disease, having COVID-19 could be like pouring more fuel on that ‘fire’ in the brain,” Professor Woodruff said.
“So would a predisposition to Alzheimer’s disease and other inflammasome-related dementias.”
But the study also found a potential treatment.
The researchers administered a class of inhibitor drugs developed by UQ that are currently in clinical trials in patients with Parkinson’s disease.
“We found that it successfully blocked the inflammatory pathway activated by COVID-19, essentially putting out the fire,” Dr. Albornoz Balmaceda said.
“The drug reduced inflammation both in mice infected with COVID-19 and in microglia cells from humans, suggesting a possible therapeutic approach to prevent neurodegeneration in the future.”
Professor Woodruff said that while the similarity between how COVID-19 and dementia diseases affect the brain was concerning, it also meant that a possible treatment already existed.
“Further research is needed, but this is potentially a new approach to treating a virus that could otherwise have untold long-term health ramifications.”
The research was co-led by Dr Alberto Amarilla Ortiz and Associate Professor Daniel Watterson and involved 33 co-authors across UQ and internationally.
About this COVID-19 and neuroinflammation research news
Author: Press office
Source: University of Queensland
Contact: Press Office – University of Queensland
Image: Image is in public domain
Original research: Free access.
“SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia via spike protein” by Eduardo A. Albornoz et al. Molecular psychiatry
SARS-CoV-2 drives NLRP3 inflammasome activation in human microglia through spike protein
Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, a growing number of reports indicate that SARS-CoV-2 infection can also cause serious neurological manifestations, including precipitating cases of probable Parkinson’s disease.
As microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, here we asked whether SARS-CoV-2 could promote microglial NLRP3 inflammasome activation.
Using SARS-CoV-2 infection of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as a preclinical COVID-19 model, we have established the presence of the virus in the brain as well as the microglial 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 and enter human microglia in the absence of viral replication.
This interaction of virus and microglia directly induced robust activation of the inflammasome, even in the absence of another priming signal. Mechanically, we demonstrated that the purified SARS-CoV-2 spike glycoprotein activated the NLRP3 inflammasome in LPS-primed microglia in an ACE2-dependent manner.
The spike protein could also prime the inflammasome in microglia via NF-κB signaling, allowing activation via ATP, nigericin or α-synuclein. Notably, SARS-CoV-2 and spike protein-mediated microglial inflammasome activation was significantly enhanced in the presence of α-synuclein fibrils and was completely suppressed by NLRP3 inhibition.
Finally, we demonstrate 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 findings support a possible mechanism of microglial innate immune activation by SARS-CoV-2, which may explain the increased vulnerability to the development of Parkinson’s disease-like neurological symptoms in individuals infected with COVID-19, and a potential therapeutic avenue for intervention.