Infections of the central nervous system have been associated with an increased risk of developing neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). One virus that can infect the central nervous system is the SARS-CoV-2 virus, which brought about the coronavirus pandemic in 2019. Researchers became interested in the virus’s ability to infect brain cells because neurological symptoms such as headaches, fatigue, and neurocognitive symptoms such as brain fog, are common among COVID-19 patients.
In her doctoral thesis, Doctoral Researcher Pinja Kettunen investigated the ability of SARS-CoV-2 to infect neurons and to induce neurodegenerative changes. In addition, Kettunen's doctoral thesis uncovered the route the virus uses to enter neurons.
Kettunen and other international researchers have found that SARS-CoV-2 can infect a small subset (<1%) of human neurons. However, its infection potential is low compared to other neurotrophic or “neuron-seeking” viruses such as human herpes viruses and the tick-borne encephalitis virus.
Viral route to human neurons discovered
According to Kettunen, the drug apilimod dimesylate and compounds that inhibit the function of cathepsin enzymes blocked SARS-CoV-2 infection in neurons in cell cultures. In contrast, compounds that inhibit the function of similar enzymes on the cell surface were not effective. These findings suggest that the virus infects human neurons via the so-called endolysosomal pathway, where the virus is first taken up into an intracellular structure known as an endosome. In the endosome, enzymes such as cathepsins cleave the viral surface proteins resulting in the release of the viral genome into the cytoplasm of the host cell. In the cytoplasm, the virus harnesses the host cell’s internal mechanism to produce new viruses.
Potential link between infection and neurodegenerative diseases
While the ability of SARS-CoV-2 to infect human neurons is weak, Kettunen and others have found that these infections can cause changes associated with neurodegenerative diseases such as the accumulation of harmful proteins, the secretion of inflammatory mediators, and the death of infected neurons. For example, Kettunen observed in her doctoral thesis that phosphorylated tau proteins accumulate in infected neurons – a process which is also common in neurodegenerative diseases such as Alzheimer’s disease.
“In the future, it will be important to determine whether the neurological symptoms seen in COVID-19 patients are caused by inflammation originating from outside the central nervous system or by direct infections of the brain. It would also be important to investigate whether SARS-CoV-2 infection can exacerbate the progression of already existing neurodegenerative diseases,” Kettunen muses.
Public defence:
Pinja Kettunen, MSc, defended her doctoral thesis entitled ‘Severe acute respiratory syndrome coronavirus 2 entry into human induced pluripotent stem cell-derived neurons and consequences to the host cell’ on 5 March 2025 at 17.00 at the Faculty of Biological and Environmental Sciences, University of Helsinki. The public defence took place in Biomedicum, hall 2, Haartmaninkatu 8.
Professor Søren Riis Paludan from Aarhus University served as the opponent and Francisco Rivera Gomez-Barris as the custos.
The doctoral thesis is also available in electronic form through the Helda repository.
Contact info: pinja.kettunen@helsinki.fi
Viral, bacterial, fungal, and parasitic infections of the central nervous system have been suggested to increase the risk of developing neurodegenerative diseases. In particular, the link between the herpes simplex virus 1and Alzheimer’s disease has been extensively investigated. For now, no direct causality has been demonstrated between a specific pathogen and a neurodegenerative disease. Instead, it seems that several different pathogen infections can cause inflammation of the nervous system, which, if prolonged, can lead to degenerative diseases. In addition, it is likely that people who develop neurodegenerative diseases also carry other susceptibility factors, such as genetic mutations, that make them vulnerable to the harmful effects of infections and central nervous system inflammation.