Several months after contracting Covid-19, symptoms can persist in some patients. Scientists from the Institut Pasteur show in an animal model that SARS-CoV-2 infects the brain and persists for up to 80 days after the acute phase of the infection in a part of the brain called the brainstem.
The presence of the virus is linked to signs of depression, memory disorders, and anxiety. Genes related to metabolism and neuron activity are disrupted in the brains of these animals, in a way similar to what happens in neurodegenerative diseases.
The persistence of certain symptoms several weeks, or even months, after Covid-19 infection was observed as early as the first epidemic wave. This phenomenon, now called "Long Covid" (or Post-Covid-19 Syndrome), is characterized by a series of symptoms that generally appear within three months of the initial illness and last for at least two months.
Long Covid affected 4% of the French adult population at the end of 2022 according to estimates from Santé publique France. The most frequent chronic and disabling symptoms of Long Covid are: profound fatigue, neurological disorders ("brain fog"), respiratory difficulties (shortness of breath, tachycardia), or headaches.
Researchers from the Lyssavirus, Epidemiology and Neuropathology unit at the Institut Pasteur had previously shown that the olfactory epithelium could constitute an entry point for the virus into the brain and could explain some of the neurological manifestations of Long Covid. In this study, the scientists followed the effects of SARS-CoV-2 infection on the central nervous system up to 80 days after the acute phase of the infection in the animal model.
The researchers detected viral RNAs of SARS-CoV-2 in the nervous system, more specifically in a part of the brain called the "brainstem", in most infected animals and for all the studied Sars-CoV-2 variants (Wuhan, Delta, Omicron BA1), 80 days after the acute phase of the infection. Additional analyses highlighted the virus's replication activity in the tissues, which implies that the virus can continue to infect new cells, although the viral load is low. The virus could thus persist "at a low level" in the brainstem.
The researchers then studied the consequences of these viral RNAs on brain metabolism. They observe that genes related to metabolism and neuron activity are disrupted in the brains of these animals, in a way similar to the molecular signatures of neurodegenerative diseases, notably Parkinson's disease with the dysregulation of the dopamine pathway.
Long Covid: SARS-CoV-2 persists long-term in the brainstem and disrupts neuron activity. Fluorescence microscopy of cells infected with the SARS-CoV-2 virus isolated from the brain of an infected hamster. Two viral proteins are marked: spike (green) and nucleoprotein (pink). Cell nuclei are marked in blue.
© Anthony Coleon - Institut Pasteur "
We observed that the expression of genes related to dopamine metabolism is altered. Sars-CoV-2 infection appears to have an impact on the production of dopamine, a neurotransmitter involved in the regulation of emotions and memory," explains Anthony Coleon, first author of the study and a PhD student in the Lyssavirus, Epidemiology and Neuropathology unit at the Institut Pasteur.
The scientists also observe that the presence of the virus, 80 days after the acute phase of the infection, is linked to signs of depression, memory disorders, and anxiety. Furthermore, the evaluation of these symptoms revealed a difference in behavioral symptoms depending on the sex of the animals.
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Our study highlights for the first time, in an animal model, the long-term biological consequences of Sars-CoV-2 infection. It suggests biological signatures that could explain some of the persistent symptoms observed in patients," continues Guilherme Dias de Melo, principal author of the study and a researcher in the Lyssavirus, Epidemiology and Neuropathology unit at the Institut Pasteur.
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We are continuing our work to understand how the infection induces the loss of function in dopamine neurons. Our study has identified a list of genes dysregulated long-term by SARS-CoV-2 infection. These genes constitute potential targets for the search for therapeutic molecules," he concludes.
This study was published on July 22, 2025, in
Nature Communications.