STTT: Chinese scientists released autopsy reports on the brains of new crown infected patients, and found that monocytic encephalitis and blood-brain barrier damage were found in clinical findings

*For medical professionals only

Recently, the impact of the new crown on the heart and nervous system has received widespread attention
.

Not long ago, we introduced an autopsy study published in Nature by Daniel S.
Chertow's team at the National Institutes of Health (NIH): the new coronavirus can persist in human tissues such as the brain for up to 7 months [1].

However, this study did not study the histopathological changes
in the brain after infection with the new crown.

Recently, a research team led by Bian Xiuwu of the First Affiliated Hospital of University of Science and Technology of China/Southwest Hospital of Army Medical University, Leng Ling of Peking Union Medical College Hospital, and Ping Yifang and Yao Xiaohong of Southwest Hospital of Army Medical University published important research results in the famous journal Signal Transduction and Targeted Therapy [2].

They compared the brain autopsy results of 9 severely ill new crown infected people (who died in 2020) and 9 age-matched healthy people, and found that microglia and astrocytes were widely activated in the brains of new crown infected people, the blood-brain barrier (BBB) was severely damaged, and there was a variety of monocytes and T lymphocytes infiltrate
.

This study has given us a better understanding of the new crown infection and also provides a potential target for the treatment of related symptoms
.
It is understood that this is also the first study to compare the brains of people infected with the new crown with the normal brains of age-matching.

▲Screenshot of the first page of the paper

There have been many studies that show that the new coronavirus can infect the brain [1], and even studies have found encephalitis and/or meningoencephalitis in the brain of infected people [3].

However, there has been no comprehensive analysis
of brain inflammation and infiltrating immune cells associated with COVID infection.

In order to better understand the impact of the new crown virus infection on the brain, Bian Xiuwu and others conducted autopsies on the brains of 9 severely infected people in Wuhan in 2020, with patients aged between 57 and 87 years old, and the median age was 77 years old
.
As a control, they also studied the brains
of 9 normal donors between the ages of 50-70.

Unlike Chertow's team, Bian Xiuwu's team found no mRNA or viral protein
for the new coronavirus in neurons and glial cells in all brain tissue samples.
However, in the brains of new crown infected people, they found neurotropic phenomena (nerve cells are engulfed by glial cells) and microglial nodules; These two phenomena
are not found in the brain of a normal donor.

▲Neurophilic phenomena (upper left) and microglial nodules (bottom left)

In addition, compared with the normal control group, the number of activated microglia in the brain of the new crown infected person with increased soma was significantly increased; Moreover, there is an increase in astrocytes expressing the glial fibrous acid protein GFAP, which also means that astrocytes are widely activated
.

Quantitative analysis of immune cells found that compared with the control group, the number of IBA-1+ microglia, CD16+ and CD14⁺ monocytes infiltrated in the brains of new crown infected patients increased
significantly.
Moreover, these inflammatory cells are mainly increased
in the perivascular space and parenchyma (especially around necrotic neurons) in the temporal lobe, frontal lobe, brainstem, and medulla oblongata.

The above results show that brain inflammation associated with new crown infection does exist, and it is encephalitis
dominated by monocytes.

▲Infiltration state of monocytes

In order to understand the neuroinflammatory pathways of monocytic encephalitis associated with new crown infection, Bian Xiuwu's team analyzed proteome data
from two sets of brains.

In total, a total of 572 proteins were expressed
differently between the brains of the control group and the brains of the new crown infected people.
Specifically, immune signaling pathway-related proteins that drive the release of inflammatory factors, such as JAK-STAT signaling pathway protein and monocytes chemotaxis protein 1 after IL-12 stimulation, are upregulated
in the brains of new crown infected patients.

The research team believes that from the proteome data, microglia and astrocytes in the brains of new crown infected people are activated, releasing inflammatory mediators (IL-4/6/12, etc.
) to cause brain damage
.

▲Proteomics research data

The results of electron microscopy showed that the blood-brain barrier of the new crown infected patients was damaged, which was manifested by swelling of capillary endothelial cells, abnormal tight junctions, rupture of the basal layer, and expansion of the glial membrane
.

In addition, the brain of new crown infected people also has angiogenic cerebral edema, and the degree of cerebral edema is significantly related
to the damage of the blood-brain barrier and the activation of astrocytes.
They also detected the new coronavirus protein
in brain endothelial cells.

Based on these findings, they believe that the integrity of the blood-brain barrier in people infected with the new crown is broken, and there is a viral infection
in the cerebral blood vessels.

▲Damaged blood-brain barrier under electron microscopy

After comparing the cytokine profiles that cause encephalitis associated with the new crown infection with those that cause lung and liver damage, Bian Xiuwu's team found that the brain, lung and liver tissues of new crown infected people contained more IL-1, IL-8, IL-12, IL-18 and TNF-α, which means that these pro-inflammatory cytokines may contribute to the occurrence
of systemic inflammatory storms.

▲ New crown infection-related encephalitis has a similar inflammatory factor map to lung and liver injury

At the end of the study, Bian Xiuwu's team also analyzed the neuropathological phenomenon of pneumonia in the brains of new crown infected people
.

Neuronal necrosis, cytosolic Nissl dissolution/disappearance, and the formation of giant neurons were found in the gray matter of the brains of new crown-infected people; In the white matter of the brain, they found that the myelin sheath swelled, ruptured, or disappeared
.
Multiple cystic softening foci
were also found in the brains of 5 people infected with the new crown.

When analyzing the changes in non-inflammatory signaling pathways in the brains of new crown-infected patients, elements of nervous system development, retrograde neuronutrient signaling, neuroprotection and brain-derived neurotrophic factor signaling pathways were found to be downregulated
.

Changes in non-inflammatory signaling pathways in the brain

Overall, this study tells us that the effects of COVID infection on the brain are broad and deep
.
In addition, this study not only determined the histopathological and molecular characteristics of monocytic encephalitis associated with new crown infection, but also provided potential targets for future treatment
.

It should be pointed out that this study was carried out in the brains of early infected people in 2020, and the impact of the currently circulating Omicron strain on brain pathology needs further research
.

References:

[1].
Stein SR, Ramelli SC, Grazioli A, et al.
SARS-CoV-2 infection and persistence in the human body and brain at autopsy.
Nature.
2022; 612(7941):758-763.
doi:10.
1038/s41586-022-05542-y

[2].
Zhang PP, He ZC, Yao XH, et al.
COVID-19-associated monocytic encephalitis (CAME): histological and proteomic evidence from autopsy.
Signal Transduct Target Ther.
2023; 8(1):24.
doi:10.
1038/s41392-022-01291-6

[3].
Pilotto A, Odolini S, Masciocchi S, et al.
Steroid-Responsive Encephalitis in Coronavirus Disease 2019.
Ann Neurol.
2020; 88(2):423-427.
doi:10.
1002/ana.
25783

The author of this article BioTalker