The brain’s choroid plexus is a structure that provides a physical barrier between the blood and the cerebrospinal fluid surrounding the brain. The choroid plexus supplies nutrients and other essential molecules from the blood to the brain and prevents viruses and bacteria from entering the brain. The choroid plexus epithelium responds to immune signals from the brain and circulation, generates its immune signals, and is responsible for removing toxins from the brain into the blood. Decreased functions of the choroid plexus—for example, in infections, inflammation, aging, and neurodegeneration—can impair brain immune responses, leading to cognitive decline.

Although the choroid plexus can destroy viruses before infecting the brain, its protective activity can also negatively affect it. So, in some patients, after recovery from coronavirus, persistent cognitive impairment is observed.

Possible causes of cognitive decline after a viral infection:

  • direct damage to the brain by the virus;
  • the body’s reaction to the virus.

Scientists from the Weizmann Institute of Science in Israel have found an association between cognitive impairment after severe coronavirus infection and an antiviral type I interferon (IFN) response in the choroid plexus epithelium. The protective response of IFN is the body’s natural reaction to viruses. But if the IFN response persists for a long time, it impairs brain function.

Direct Brain Damage by The Virus is Unlikely

The choroid plexus is one of the sites through which the coronavirus can enter the brain. However, direct viral damage to neurons is controversial because coronavirus RNA or proteins are rarely found in brain samples from patients who have died from COVID-19. In addition, detecting coronavirus RNA or proteins is not associated with neurological symptoms.

In a mouse study, the coronavirus spike protein accumulated in several body areas, including the choroid plexus, but was not found in brain tissue or cerebrospinal fluid.

The coronavirus uses the ACE2 receptor located on the cell surface to enter. Epithelial cells of the choroid plexus have more ACE2 receptors on their surface than neurons and their surrounding cells. Therefore, the likelihood that the coronavirus will infect the epithelial cells of the choroid plexus is higher than the risk of infecting brain tissue.

The Body’s Response to The Virus: Coronavirus Disrupts The Function of The Choroid Plexus

When SARS-CoV-2 enters the choroid plexus cells, it triggers an antiviral response that blocks the virus from entering the brain.

Studies in patients who died from COVID-19 have shown that coronavirus causes choroid plexus cell death, disruption of the blood-cerebrospinal fluid barrier, leukocyte infiltration, and neuroinflammation. Impaired choroid plexus barrier function plays a vital role in the neuropathogenesis of COVID-19.

Type I Interferon in The Choroid Plexus is Associated With Cognitive Impairment

Type I IFN signaling (e.g., IFN-α and IFN-β) is a normal protective response to viral infection.

In a mouse study, the antiviral response of IFN-I at brain barriers, including the choroid plexus epithelium, was associated with cognitive impairment.

The IFN-I response is characteristic of viral infections and is also observed in aging and neurodegenerative diseases associated with cognitive decline. In a study in aged mice, IFN-I signaling in the choroid plexus was related to cognitive impairment and reduced neurogenesis in the hippocampus, the brain region responsible for long-term memory and spatial orientation. Blocking the IFN-I signal restored cognitive functions in old mice.

Analysis of brain samples from people who died from COVID-19 showed robust expression of interferon-stimulated genes in the choroid plexus but did not detect the presence of coronavirus in the brain. In the cerebral cortex, supporting cells of the nervous tissue expressed genes associated with Alzheimer’s disease, inflammation, and neuronal death. Genes related to nerve impulse transmission were also dysregulated, which may indicate a cognitive deficit.

When infected with the coronavirus, the choroid plexus sends inflammatory signals to the brain, stimulating a protective IFN-I response that will prevent the virus from spreading to the brain. However, the protective antiviral response of IFN-I in the choroid plexus epithelium can cause inflammation in the brain tissue and cognitive impairment.

Interferon-gamma Deficiency Linked to Cognitive Loss

IFN-gamma (type II interferon) is essential for normal brain function, including cognitive processes and social behavior. In addition, IFN-gamma is required for choroid plexus epithelium to express molecules that attract immune cells from the bloodstream to repair brain damage.

The type I IFN response in the choroid plexus epithelium can be enhanced by a decrease in IFN-gamma signals from the periphery coming from areas of the body outside the brain. Decreased IFN-gamma signaling in the choroid plexus is associated with aging, chronic neurodegeneration, and reduced plasma IFN-gamma expression in Alzheimer’s patients correlates with cognitive decline.

A decrease in IFN-gamma production in the periphery may result from a decline in immune functions. In some patients with COVID-19, the immune system is depleted, and IFN-gamma activity is reduced. Also, in patients with COVID-19, the level of regulatory T cells, which have an immunosuppressive effect, is increased. The increased level of regulatory T cells may be a direct consequence of increased expression of type I IFN in the periphery.

Conclusion

The coronavirus induces a type I interferon response in the choroid plexus. An uncontrolled antiviral response to IFN-I can cause cognitive impairment. The choroid plexus IFN-I response may be enhanced due to immunosuppression and reduced IFN-gamma activity in patients with COVID-19.

Restoring systemic immunity after recovering from coronavirus may prevent cognitive impairment. Such treatment should be given after the acute phase of infection to avoid severe COVID-19.

To combat neurodegeneration, IFN-gamma signaling in the choroid plexus can be enhanced by blocking immune checkpoints in the periphery. Blockade of immune checkpoints is one of the methods for treating tumors. You can read more about it in the article “Microbiota to Defeat Cancer: Intestinal Bacteria Regulate The Anti-Cancer Response in The Tumor Microenvironment.

In a study in mice with Alzheimer’s disease, blockade of immune checkpoints induced a systemic interferon-gamma response that cleared amyloid plaques and improved cognitive function.

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Reference

The type I interferon antiviral response in the choroid plexus and the cognitive risk in COVID-19

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