The coronavirus pandemic has increased general interest in how viruses enter the brain, and what their effects on the brain are.
“There are receptors on the surface of some brain cells which allow the coronavirus to penetrate the cell,” Academy Research Fellow, Associate Professor Katja Kanninen said in a Brain Awareness Week webinar.
Held on 16 March, the theme of the webinar was COVID-19 and the Brain, and it was organised by the Finnish Brain Council, the Brain Research Society of Finland, Aalto University, the University of Eastern Finland, the Doctoral Programme Brain&Mind at the University of Helsinki, Helsinki Network Brain and Mind, and Neurocenter Finland.
Katja Kanninen is the leader of a research group addressing the neurobiology of brain diseases at A.I. Virtanen Institute for Molecular Sciences in the University of Eastern Finland. Cell models developed by the group can also be used to investigate the effects of a viral infection on brain cell function.
“Viruses are thought to have several routes to the brain, and one of them is through the nose. When we breathe in air, viruses may end up in the olfactory epithelium in the mucous membrane of the nose, which is directly connected to the brain.”
The research group models viral infections in cell culture experiments using co-cultures of human olfactory epithelium cells and brain cells, as well as exposures at the interface of air and fluid.
“We seek to develop models that correspond, as well as possible, to the real conditions in which humans get exposed to viruses.”
At the webinar, Kanninen talked about what is currently known about the effects of viruses on brain cells. The objective of viruses in general is to invade our cells, because they need a host cell for their reproduction – ultimately turning the host cell into a virus factory. Virus replication interferes with the host cell’s function and may even lead to cell death.
“The virus penetrates the cell using a receptor protein on the cell's surface. The SARS-CoV-2 virus causing the current pandemic can bind to the ace-2 receptor, for example. Small numbers of this receptor have also been found on the surface of nerve cells, indicating that the virus can also penetrate neurons.”
In addition to olfactory epithelium cells, i.e. the exposure route studied by Kanninen, viruses may also enter the brain through the bloodstream.
“In some cases, they can enter the brain tissue directly through the blood-brain barrier, or they can use immune system cells as transporters. Another possible route is through the intestine, and plenty of research into the gut-brain connection is being conducted also otherwise.”
“If the virus enters the brain, there, too, it will try to infect cells and replicate itself in them. Besides neurons, the virus can also affect microglia, which act as immune cells in the brain, and astrocytes, which act as support cells.”
The viral infection can also cause indirect harm to the brain. If, for example, lung function is disturbed, brain cells, too, will suffer from the resulting lack of oxygen. The viral infection can also lead to hyperactivation of the body’s immune system and, consequently, to inflammation that affects the brain.
“However, a more detailed analysis of these effects still requires a lot of research,” Kanninen pointed out.
Among other things, the webinar audience was interested in whether age plays a role in how effectively viruses can enter the brain. According to Kanninen, studies have shown that ageing and neurological disorders weaken the function of the blood-brain barrier that protects the brain.
“This is thought to be one of the reasons why older people are more at risk in terms of COVID-19.”
However, it is not possible to look for the virus, or parts of it, in the brain of a living person.
“The virus, or parts of it, can only be found after autopsy, when the brain tissue can be examined with a strongly magnifying electron microscope. In studies published so far, there is great variation in whether the virus has been found in the brain of those who have died of COVID-19: in one study, the virus was found in as many as half of the subjects, whereas in other studies it has only been found in a small percentage, or not at all.”
According to Professor of Virology Olli Vapalahti from the University of Helsinki, the SARS-CoV-2 virus is highly infectious because it uses a two-receptor tactic, entering the cell via both the ace-2 and neuropilin 1 receptors.
“If a cell contains the protein neuropilin 1, this scales up the infection in contrast to a situation where the virus can only use the ace-2 receptor to enter the cell.”
Vapalahti notes that neuropilin 1 is found especially in developing blood vessels, in certain immune cells, in the upper respiratory tract and the olfactory epithelium, as well as in the nerve endings of developing neurons.
“Indeed, this seems to provide the virus with an infectious pathway from the olfactory epithelium to the olfactory bulb, and from there to the central nervous system.”
What do we currently know about neurological and prolonged symptoms?
“Neurological symptoms have also been observed in people with COVID-19,” Eemil Partinen, Specialising Physician in Neurology at Helsinki University Hospital, says.
“They have, however, mainly been studied in hospitalised patients, who are usually older and who often have comorbidities and pre-existing neurological conditions.”
In an acute disease, the most common neurological symptoms include headache, impaired consciousness, smell and taste disorders, acute cerebrovascular disorders, and dizziness. According to Partinen, the risk of cerebrovascular disorders may be increased by COVID-19-associated increased coagulation activity and inflammation of vascular endothelial cells.
After the acute phase of the disease, some patients have experienced sleep disorders, fatigue, palpitations, “brain fog”, and other symptoms that resemble the chronic fatigue syndrome. Some patients have also developed preliminary symptoms of Parkinson’s disease.
In the webinar, Professor of Anatomy Seppo Parkkila from Tampere University shed light on what is known as long COVID. In addition to the acute COVID-19 infection, the Finnish disease classification system was recently updated to include the post-COVID-19 condition, and the multisystem inflammatory syndrome associated with COVID-19, as independent diagnoses. According to a British definition, the acute phase of COVID-19 lasts up to 4 weeks. A disease lasting for 4-12 weeks is prolonged COVID-19 and, if symptoms persist for more than 12 weeks, the term post-COVID-19 syndrome is used.
According to Parkkila, the most common symptoms of prolonged COVID-19 are shortness of breath, sore throat, coughing, nausea, lack of smell and taste, muscle pain, headache, fatigue and fever.
“Symptoms can develop in many different organ systems. In part, this is likely due to the fact that the virus can, through its receptors, access many different organs.”
The prevalence of long COVID has varied in different studies. In a study conducted in the UK, the US and Sweden, 13% of patients had symptoms for more than 4 weeks, 5% for more than 8 weeks, and 2% for more than 12 weeks. More than five symptoms during the first week predicted a higher risk of prolonged disease. However, prolonged symptoms have also been observed in patients whose disease was mild or asymptomatic.
There is no specific treatment for prolonged COVID-19, but according to Parkkila, patients can be assisted by symptomatic treatment, monitoring and, if necessary, psychological support and rehabilitation.
“Globally, there will be a large number of these patients in the future, and it will probably be necessary for every country to take a stand on how to best treat them.”
