“ We hope to provide relief to patients who have been told they are not sick, that it is 'in their head'. What we are showing in the lab is that long Covid has a biological cause!", says Guilherme Dias de Melo, veterinarian and researcher in infectious diseases and neuropathologies at the Pasteur Institute. Eighty days after the initial infection, the Covid-19 virus was found, still infectious, in the brainstem of hamsters affected by symptoms similar to those of long Covid, demonstrates the work he led and published in the journal Nature Communications.
Anxiety, depression and memory problems
“ Animals infected 80 days earlier had the virus still infectious in the brain, where several metabolic pathways were disrupted, showing that the virus is responsible for the symptoms.", explains Guilherme Dias de Melo. These symptoms, which were only exhibited by hamsters infected with SARS-CoV-2 (the Covid-19 virus), included anxiety, depression and memory problems, just like patients suffering from long Covid. The study confirms in passing that the hamster, which unlike the mouse has the same ACE2 receptors as humans serving as a gateway for the virus, is one of the first reliable animal models of long Covid.
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The virus, still infectious, is hidden in the brainstem
At the base of the brain of animals infected for several weeks, researchers found the virus's RNA in the brainstem, but in such small quantities that they were barely detectable. Yet, once isolated, these viruses were still perfectly capable of infecting other cells 80 days after the initial infection—a period that, compared to the life expectancy of hamsters, could represent human years.
“ So we have a virus that survives, that multiplies quietly: that's the most astonishing part!“, comments Guilherme Dias de Melo. “ SARS-CoV-2 is capable of invading the brain very early, from the start of the acute phase, but for reasons that are not yet understood, it does not spread everywhere as in the lungs, it remains in small quantities in this reservoir"The reasons for this viral confinement are the team's next research topic." Perhaps the brain is not a suitable environment for the spread of these viruses, for example because ACE2 receptors are not expressed in sufficient quantities there as in the lungs, or because the metabolism of cells and the immune response are different there.“, suggests Guilherme Dias de Melo.
Dopamine and glutamate, two neurotransmitters affected in long Covid
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Hidden in the brainstem, the virus causes visible inflammation through activation of the innate immune system—the frontline. Another consequence is that this discreet infection disrupts the expression (activation level) of several hundred genes, either up or down. For about a hundred of them, the difference is more than double (or, for a minority, half) the normal level. The deregulation of these genes indicates a problem in neuron communication“, interprets Guilherme Dias de Melo.
These genes are involved in the production of two neurotransmitters and associated receptors that enable communication between neurons: glutamate and dopamine, and also in the production of energy necessary for the proper functioning of these neurons. The most abundant neurotransmitter in the brain, glutamate, when deregulated, is a sign of poor brain health. As for dopamine, it is linked to emotions, memory, and learning, which are precisely disrupted in patients with long-term Covid.
Commonalities with neurodegenerative diseases
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“ What's even more interesting is that the neurons that produce dopamine are few in number and located in a very specific area of the brainstem. These are precisely the ones that are destroyed in Parkinson's disease.", explains Guilherme Dias de Melo. This work therefore reveals important common points between long Covid and the large family of neurodegenerative diseases. " Neurons of infected animals have deficient energy production, with a very present inflammation and innate immune response, and a deregulation of neurotransmitter metabolism.“, lists Guilherme Dias de Melo. “ Energy, communication and inflammation are three points that are also at the basis of neurodegenerative diseases.. »
Of course, this does not mean that long Covid causes Parkinson's disease or any neurodegenerative disease, but that these two pathologies are linked to similar mechanisms. Based on this observation, other links could exist. Could viral infection be a trigger for a process in the brain that can lead to these diseases? Or could it persist and cumulatively promote the onset of a neurodegenerative disease?", asks Guilherme Dias de Melo. Further studies will have to explore these possibilities by observing the evolution of the infection over the longer term, with the idea of possibly transposing treatments from one pathology to another.
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