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The 2019 coronavirus disease (COVID-19) pandemic has claimed more than 2.4 million lives, but its long-term sequelae are still being identified. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) produces an infection that can be associated with a broad spectrum of illnesses, from asymptomatic respiratory failure to critical or terminal respiratory failure or multi-organ dysfunction .
A new pre-print on the bioRxiv * The server describes the results of a study in macaques which showed the development of neurological features of inflammation following infection with SARS-CoV-2.
Neurological symptoms of SARS-CoV-2 infection
SARS-CoV-2 primarily affects the respiratory organs, but in about a third of COVID-19 hospital patients, neurological manifestations are present. These include anosmia or dysgeusia, delirium, disturbances of consciousness, seizures or psychosis. Some patients also develop parkinsonism.
Neurological symptoms may be due to infection of the brain with the virus or activation of immune cells induced by the virus. More evidence is needed to reach a conclusion on this issue in human infection with SARS-CoV-2.
The long-term effects on the central nervous system (CNS) following this infection, even with mild to moderate COVID-19, are poorly understood, although they are likely to be present in most patients.
Study objectives
In order to explore this, the current study was performed in a controlled design on two species of macaques, rhesus macaques and cynomolgus macaques.
After inoculation with SARS-CoV-2 in monkeys through a combination of intratracheal and intranasal routes, the researchers found that viral RNA was found in tracheal and nasal swabs for up to ten days. All of the monkeys had mild to moderate illness.
Increased brain metabolism
The researchers also followed the animals with weekly PET-CT scans of the brain after the virus had disappeared from the respiratory samples. They found that two of the four monkeys exhibited increased uptake of the tracer into the pituitary gland at many points.
Absorption of the tracer is an indicator of metabolic activity. The metabolic activity of the pituitary is generally similar to the background metabolism of the brain.
In one animal, absorption of the tracer increased from day 8 to the last examination on day 35. This indication of higher metabolic activity could be due to a direct infection of the pituitary gland, or an indirect effect of the pituitary gland. pituitary inflammation, or as a result of hypothalamic acid. pituitary dysfunction. Interestingly, no COVID-19 patient with an active infection has low cortisol levels indicating poor pituitary function.
Viral RNA in brain tissue
After euthanizing the animals 5-6 weeks after infection, the researchers found that viral RNA was detectable (using a real-time quantitative polymerase chain reaction, RT-qPCR) in many parts of the right brain. in cynomolgus macaques.
These included the cerebellum, medial motor cortex, sensory cortex, and basal ganglia. The pituitary, olfactory bulb, substantia nigra, medulla oblongata, pons, nucleus caudatus, and putamen did not show immunological markers for viral RNA.
No evidence of viral replication
Subgenomic RNA was not present, indicating that viral replication was not occurring in the brain at this stage. Viral antigens were also not detected in any animal.
Inflammation of brain tissue
Inflammation was observed in the brains of all infected macaques. T lymphocyte infiltration was also present in the brain parenchyma, which may indicate that the T lymphocytes crossed the blood-brain barrier after infection.
Microglial activation was also present in different areas of the brain, including the pituitary gland and the olfactory bulb, but at a low level. No B lymphocytes were found, nor any signs of ischemia or cerebral necrosis.
Lewy bodies
Macaque brain tissue also contained Lewy bodies, or α-synuclein deposits, which in humans have been linked to Parkinson’s disease or Lewy body dementia. These were found in the midbrain of all rhesus macaques and one aged cynomolgus macaque, but none of the controls.
Overview of CNS Effects of SARS-CoV-2 Exposure in Macaque Brain. The presence of viral RNA was studied in several regions of the brain as indicated by the numbers. Regions positive for cynomolgus C3 macaque viral RNA are indicated by a yellow background. The brain regions analyzed are indicated by a number. Areas of the brain with T lymphocytes (CD3 +) and activated microglia (Mamu-DR +) are shown respectively in light blue (light expression) and dark blue (moderate expression). Lewy body areas of the brain (α-synuclein +) are shown in orange.
What are the implications?
This shows that SARS-CoV-2 causes inflammation in the macaque’s brain. The presence of viral RNA also indicates that the virus is neuroinvasive.
Critically ill COVID-19 patients have shown signs of neuropathology. In contrast, the macaques in this study had only mild or moderate symptoms of infection, but brain damage was present.
The virus entry route into the brain could be the olfactory bulb or other neural pathways, such as infected sensory or motor neurons, thus reaching the pituitary gland, which has the virus entry receptor, the enzyme converting angiotensin 2 (ACE2).
In fact, in all infected macaques, there was evidence of immune activation in the olfactory bulb, as evidenced by the presence of microglia or activated T cells.
If the virus is carried in neurons, this could also explain the development of Parkinson-like symptoms. The virus could also reach the substantia nigra, linked to Parkinson’s disease, by retrograde transport.
This region is found in the ventral midbrain, where Lewy bodies have been found in macaques. These accumulations of misfolded proteins in inclusion bodies are associated with Parkinson’s disease or Lewy body dementia in humans.
Based on their findings, the researchers question whether they have any predictive value for the long-term development of these disorders in COVID-19 patients, even if the infection was mild or even asymptomatic.
*Important Notice
bioRxiv publishes preliminary scientific reports which are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behaviors, or treated as established information.
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