More than 54 million people worldwide, including one million in France, suffer from the effects of SARS-CoV-2 long following infection. Jean-Marc Sabatier* helps us better understand this strange disease.
What is the long Covid called?
J.-M. Sabatier– We speak of long Covid when people infected with SARS-CoV-2 show symptoms and disorders of Covid-19 more than four weeks following the start of their infection. 54 million people are affected worldwide, including around one million in France.
What are the symptoms of long Covid?
J.-M. S. They are multiple. The most frequently encountered are fatigue, neurological disorders (cognitive, sensory, headache), disorders of smell (anosmia), taste (ageusia). But also cardio-thoracic disorders (tachycardia, dyspnea), cough, palpitations… Digestive (diarrhea) and ophthalmological disorders, skin problems (hives, chilblains, itching), joint, tendon and/or muscle pain, insomnia, tinnitus, vertigo, nausea, anxiety, irritability and odynophagia. More than a hundred symptoms are listed.
Beyond four weeks following infection, these symptoms are not necessarily permanent. They can appear, disappear, come back.
What, in your opinion, are the origins of the long Covid?
J.-M.S. Several tracks have been described on the origin of the long Covid. One of them is the presence of the latent SARS-CoV-2 virus in the body which has not been completely eliminated (chronic viral infection with more or less transient reactivations) with its deleterious effects on the body.
Another track is the hyper-inflammation induced by SARS-CoV-2 which would lead to the reactivation of endogenous microbes (example: the Epstein-Barr virus, from the herpes family, present in 95% of the adult world population ) leading to deleterious effects on the organism.
Are these the only two tracks of the origin of the long Covid?
J.-M. S. Not quite. Long Covid might be associated with the presence of autoimmune antibodies directed once morest one or more host proteins (such as coagulation factor VIII, blood platelet protein PF4 and others). Including autoimmune antibodies directed once morest the renin-angiotensin system (RAS), including antibodies to the ACE2 receptor (which is the receptor for the virus), and/or anti-angiotensin-2 (an excess of angiotensin-2 overactivates the AT1R receptor causing Covid-19 diseases), etc. These autoimmune antibodies can disrupt metabolic pathways and physiological processes involved in the functioning of organs and tissues. These antibodies would thus be responsible for deleterious effects resulting from these disturbances or dysfunctions.
A long Covid might also result from a combination of these possibilities leading to multiple symptoms and disorders (more or less strong and potentially variable over time).
Why do we know so little regarding the long Covid?
J.-M. S. To date, there is little data on the long Covid. Recently, hypoactivity of the brain detected by brain imaging has been described in people suffering from long Covid. The involvement of ryanodine-sensitive (RYR) calcium channels has also been observed. RYR ion channels are found in skeletal muscle (RYR1), myocardium (RYR2), and brain (RYR3).
In my opinion, the long Covid is a persistence of symptoms or diseases of Covid-19 which would have as its main origin the dysfunction (induced by the SARS-CoV-2 virus) of the renin-angiotensin system (RAS).
The ARS plays a key role in the functioning of the human body (and mammals in general). It is particularly involved in renal, pulmonary and cardiovascular functions and controls innate immunity and the intestinal microbiota. It is found in many tissues and organs including the heart, lungs, liver, pancreas, spleen, kidneys, gonads, adrenal glands, vascular system, skin, brain… RAS dysfunction is cause of Covid-19 disease.
Many neurological disorders are reported in the context of long Covid. What is your explanation?
J.-M. S. There is a cerebral tropism of SARS-CoV-2 and the neurological damage observed is due, in my opinion, to an action of the virus on the ARS of the central nervous system. Indeed, SARS-CoV-2 can infect nerve cells (such as neurons and astrocytes that express the ACE2 receptor) and multiply there without destroying the cells.
There are local adaptations (or variants) of RAS in the human body. The RAS of the central nervous system appears particularly different from the other local RAS of the organism, although the same actors are found there (ie the same ligands and receptors).
The AT2R receptor is very present in the brain. It is involved in the repair of damage to the brain (axonal regeneration, growth of neurites, …) and the reduction of inflammation, as well as vasodilation. In other words, the AT2R receptor has a neuroprotective effect. It promotes neuronal survival and protects once morest brain damage. The AT2R receptor opposes the deleterious effects of the AT1R receptor which is responsible for Covid-19 diseases (when it is overactivated in the presence of the SARS-CoV-2 virus).
Angiotensin-2, which belongs to the RAS, is the key to Covid-19 diseases. It is both a hormone and a neuromodulator (neuropeptide) capable of acting on AT1R and AT2R. It primarily targets AT1R but, in its absence, it targets AT2R for which it has less affinity. It is notable that certain areas of the brain are very rich in AT1R receptor, others in AT2R receptor, or both in AT1R and AT2R receptors but in variable proportions.
I would add that in long Covid patients, the infection causes disorders that sometimes resemble those observed for Alzheimer’s disease. It is notable that RAS is involved in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Schizophrenia and mood disorders.
In long Covid patients, the virus does not seem to be completely eliminated; it reactivates and its deleterious effects persist over time.
*Jean-Marc Sabatier is research director at the CNRS, doctor in Cell Biology and Microbiology, affiliated with the Institute of Neuro Physiopathology (INP), at the University of Aix-Marseille.
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