PNAS: The new coronavirus affects brain function by infecting astrocytes in the human brain

Since the beginning of the new crown pandemic, studies have shown that some new crown patients have neurological sequelae, such as brain fog, headaches, inability to concentrate, and so on
.
Many subsequent studies have looked at the effects of the new coronavirus on the brain, whether and how the new coronavirus infects brain cells
.

In August 2020, Professor Huang Jiandong of Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Professor Yuan Guoyong of the University of Hong Kong, etc.
published a paper in Cell Research [1], confirming for the first time that the new coronavirus can infect human neural progenitor cells and brain organoids cultured in vitro
.

Although more and more studies have since confirmed this finding, there is still a lack of comprehensive understanding
of the cellular and molecular mechanisms involved in the human brain and its impact on brain structure and function.

Recently, the Proceedings of the National Academy of Sciences of the United States of America (PNAS) published a research paper
entitled: Morphological, cellular, and molecular basis of brain infection in COVID-19 patients.

The study describes the effects of coronavirus infection on the central nervous system of the brain and confirms that the virus is indeed able to infect and replicate in brain astrocytes, reducing the vitality
of neurons.

How the coronavirus entered the brain remains an open question
.
Some animal experiments have shown that the virus crosses the blood-brain barrier; It is also possible that the virus infected the olfactory nerve and invaded the central nervous system from there, infecting astrocytes
.
However, these are stuck in the hypothetical stage
.

Astrocytes are the most abundant central nervous system cells, and their functions include providing biochemical support and nutrients to neurons and regulating levels of
neurotransmitters and other substances that may interfere with nerve function, such as potassium.
In addition, they play an important role
in maintaining the blood-brain barrier, protecting the brain from pathogens and toxins, and helping to maintain brain homeostasis.

In the new study, the team first analyzed brain tissue samples
from a patient who died of the new coronavirus.
Of the 26 samples analyzed, 5 were confirmed to be present with the virus; Moreover, the researchers also observed signs of necrosis and inflammation, such as edema, as well as neuronal lesions and inflammatory cell infiltration in these samples
.
These changes can cause damage
to the central nervous system.
This finding supports the hypothesis that astrocytes were infected by the new coronavirus infection
.

They then used high-resolution MRIs to perform morphological analyses
of the cerebral cortex in 81 people diagnosed with mild COVID infection, 62 of whom had olfactory or taste failure 。 The analysis was performed at an average interval of 57 days after the virus was detected by qRT-PCR, and one-third of participants still had neurological or neuropsychiatric symptoms at that time, including headache (40%), fatigue (40%), memory changes (30%), anxiety (28%), loss of smell (28%), depression (20%), daytime sleepiness (25%), loss of taste (16%) and low libido (14%)
.

The researchers compared
them to 81 healthy volunteers.
The results showed that the COVID patient group showed higher levels of anxiety and depression symptoms, fatigue, and excessive daytime sleepiness
.
MRI scans showed that some COVID patients had reduced cortical thickness in certain brain regions compared to the average of the control group, and the reduced areas all occurred in the left hemisphere
.

They also observed atrophy in 28 percent of the brain's anxiety-related areas, one of
the most common COVID symptoms.
The research team said that the proportion of anxiety symptoms in new crown patients is obviously too high, and, unexpectedly, even mild patients may have these symptoms
.
In neuropsychological tests that assess cognitive function, COVID patients also performed below average
on certain tasks.

However, whether these symptoms are temporary or permanent is unknown
.
The research team found that some patients experienced improvement in symptoms, but most had persistent symptoms; Even more surprising is that many patients are also reinfected with the new variant and subsequently show more severe symptoms than when they first infected
.

According to Clarissa Yasuda, co-corresponding author of the study and professor at the Brazilian Institute of Neuroscience and Neurotechnology, "Given the current situation, we believe that longitudinal follow-up is essential to understand the evolution of neuropsychiatric changes over time and use this understanding as a basis
for developing targeted therapies.
"

The study also studied brain tissue cells and astrocytes cultured in vitro from patients who died of new coronary pneumonia to analyze how infection with the virus affects central nervous system cells
from a biochemical perspective.
The results showed changes in various biochemical pathways in the brain astrocytes of patients infected with the new coronavirus, especially those related to energy metabolism
, compared to uninfected people.

Next, they repeated the proteomic analysis in astrocytes cultured by laboratory infection and came up with similar results to autopsy studies, which also showed dysfunction
of energy metabolism.

Since astrocytes metabolism is key to supporting neuronal function, alterations in astrocytes metabolism may indirectly affect neurons
.
Metabolomic analysis results showed that one of the most critical changes in astrocytes caused by coronavirus infection is a decrease
in pyruvate and lactate levels.
Lactic acid output is one of the ways astrocytes metabolize neurons, which use as a source
of energy.
Thus, this confirms a change
in glucose metabolism.

In vitro analysis showed that lactate levels in cell culture media were normal, but lactate levels inside cells decreased
.
This means that astrocytes struggle to maintain an energy supply to neurons even after weakening their own function, but as a result, the mitochondrial function of astrocytes is altered, potentially affecting the level of
neurotransmitters such as glutamate in the brain.

In addition to observing metabolic changes that may lead to neuronal dysfunction in astrocytes infected with the new coronavirus, the research team also found that infection with the virus triggers a neurotoxic secretion phenotype in astrocytes, followed by the release of soluble factors, reducing the viability of neurons, and further leading to increased
neuronal death.
The changes in cortical thickness previously observed in COVID patients can be explained
by neuronal death as well as other mechanisms.

Because astrocytes are susceptible to the new coronavirus, the research team explored receptors that allow the virus to enter
.
Using proteomic analysis, they showed that astrocytes do not express ACE2, but they do express NRP1, which significantly enhances the ability to
infect the new coronavirus.

In summary, the results of this study are consistent with previous model results, confirming that the new coronavirus can reach the central nervous system of the patient's brain, infect astrocytes by interacting with NRP1, and then impair neuronal function and vitality
.
Therefore, these findings may provide a shortcut to treating the psychiatric symptoms caused by the new coronavirus
.