Dear Editor, 

The current pandemic is driving a dramatic shift in our lives, far beyond what we believed even acceptable until 2020. Such a great sacrifice is supposed to be necessary to protect our loved ones, the health care system and economy. Nevertheless it doesn’t come without any legitimate concerns and fears.

While the public opinion is still awaiting more data about the real implications of COVID-19 vaccines, the scientific debate has ignited over extremely conflicting conclusions. And the only measures capable to contain viral spread continue to appear to be social distancing and individual precautions (wearing proper masks, washing hands, monitoring any suspicious symptoms and so on): in other words, the maximum adherence of all to behavioural prophylaxis rules [1]. 

Nothing surprising, therefore, if many are starting to perceive this situation as an endless and frightening tunnel. For this reason, now as never before, we have a desperate need of trust. Trust in institutions, communication, research. And above all, trust in ourselves as citizens. 

I would like to spend a few words just on the last aspect of the matter. For a year and a half we have been asked to master our decisions in the most responsible and careful way. Which essentially means having the best control of our behaviour. Although it is something we take for granted every day, it may be different today despite all our efforts. Why?

My answer could sound a bit weird, or at least unusual when it comes to viruses. But for every deception there is a victim unaware of the trick: the more control he thinks he has, the less control he actually has. We represent SARS-CoV-2 mostly acting as a passive player in the so-called “host adaptation process” [2]. 

This is proven, for example, by the current discussion about how rapidly it is evolving towards more transmittive and challenging strains. Nevertheless, what I would like to point out is that we are still missing the other side of the coin: whether this virus could be capable of actively adapting the host to its own purposes. 

After all, in an evolutionary perspective it is a feature far less rare than we believe at first glance. Dr Bouayed and Dr Bohn suggested this theoretical approach for SARS-CoV-2 in their works [3]. Several parasites show the ability to manipulate host behaviour in order to improve transmission and further propagation.

Among them, some that are worth mentioning are Nematomorpha (worms), Ophiocordyceps (fungus), Plasmodium Malariae and Toxoplasma Gondii (protozoa), Wolbachia(bacteria), Rabies (virus). The mechanisms underlying their strategy are not always known, and most of the times they remain a complete secret to us as well as for their hosts. Luckily this is no more the case of rabies, thanks to the invaluable work of Dr. Hueffer and his team.  

In 2017 they discovered something astonishing: a short amino acid sequence inserted in the viral glycoprotein is able to drive behavioural modification, turning the infected animal into a frenzied and aggressive mood [4, 5, 6].

This happens due to the neurotoxic properties of the string, almost identical to the venom of some snakes. The results of the experiment showed a key role played by this “snake-like toxin" sequence in disruption of normal nicotinic receptor activity in the central nervous system, highlighting how the rabies derived peptide ( RV-183A or RV-183P) induces subtle yet decisive swings in brain communication [7]. The consequences are better verifiable looking at the following link:   

Regarding our present situation, an important issue should be raised. Indeed, the presence of a "snake like toxin" sequence seems not to be unique to the rabies virus. In May 2020 Dr. Changeaux, emeritus professor of neuroscience at the Institut Pasteur, proposed a “nicotinic hypothesis” _for COVID-19 [8]. In that occasion, he underlined how the SARS-CoV-2 Spike Glycoprotein contains a motif homologous to that of snake neurotoxins and to the RABV neurotoxin-like region.

Further in silico findings, carried out by Dr Farsalinos and his team, recognized a superposition between the peptide fragment aa375-390 and a sequence of the Neurotoxin homolog NL1 [9]. Their work strongly supported the idea that this amino acid sequence interacts with nicotinic acetylcholine receptors, and that SARS-CoV-2 itself could be deemed a blocker of their function. Something later confirmed, at the beginning of 2021, through molecular modeling and docking experiments led by Dr Alexandris and Dr Lagoumintzis [10, 11].

This feature should be considered of utmost importance now, in light of two facts. First: many studies are highlighting a surprising ability of SARS-CoV-2 in invading central nervous system tissues, suggesting that the virus can access the brain by first infecting the olfactory bulb and then spreading into the brain [12]. Such a remarkable neurotropism raises several concerns, and the research is making worldwide an extraordinary effort to investigate its consequences.   Second: the cholinergic pathway plays a critical role in modulating dopaminergic reward responses as well as locomotor behaviour, emotional state, attention, learning and memory [13, 14].   

And the lesson of rabies clearly teaches that everything capable of altering its activity could potentially gain a chance to control host behaviour. What if the virus is currently hijacking the minds of those infected, in order to make them hyperactive, anxious, impulsive, inappropriately sociable? Therefore, in the end, much more transmissive? My reasoning is highly speculative, and the only intention is to show elements that I consider of great importance and 

deserving of urgent in vivo investigation. If those who should protect others (i.e. the infected person in the paucisymptomatic state) are led by the virus not to do so, the only barrier we have available at the moment could inevitably collapse. Conversely, if we change the rules on what controls us, we will change the rules on what we can control. Thus, a crucial question to ask now is: can we trust ourselves, if infected? 

Adriano Castagna is an Italian physiotherapist, with a strong focus on spinal cord injury rehabilitation. He had the opportunity to carry out his studies at the IRCCS (Scientific Institute for Research, Hospitalization and Healthcare) Santa Lucia Foundation in Rome, where he subsequently worked in the field of neurological rehabilitation. 


[1] West R, Michie S, Rubin G J, Amlôt RApplying principles of behaviour change to reduce SARS-CoV-2 transmission. Nat Hum Behav 4, 451–459 (2020). 

[2] Simmonds P, Aiewsakun P, Katzourakis A. Prisoners of war - host adaptation and its constraints on virus evolution. Nat Rev Microbiol. 2019 May;17(5):321-328. 

[3] Bouayed J, Bohn T. Behavioral manipulation - key to the successful global spread of the new coronavirus SARS‐CoV‐2? J Med Virol. 2020 Aug 19 : 10.1002/jmv.26446. 




[7] Hueffer K, Khatri S, Rideout S, et al. Rabies virus modifies host behaviour through a snake-toxin like region of its glycoprotein that inhibits neurotransmitter receptors in the CNS. Sci Rep. 2017 Oct 9;7(1):12818. 

[8] Changeux JP, Amoura Z, Rey FA, Miyara M. A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications. C R Biol. 2020 Jun 5;343(1):33-39. 

[9] Farsalinos K, Eliopoulos E, Leonidas DD, et al. Nicotinic Cholinergic System and COVID-19: In Silico Identification of an Interaction between SARS-CoV-2 and Nicotinic Receptors with Potential Therapeutic Targeting Implications. Int J Mol Sci. 2020 Aug 13;21(16):5807. 

[10] Alexandris N, Lagoumintzis G, Chasapis CT, et al. Nicotinic cholinergic system and COVID-19: In silico evaluation of nicotinic acetylcholine receptor agonists as potential therapeutic interventions. Toxicol Rep. 2020 Dec 19;8:73-83. 

[11] Lagoumintzis G, Chasapis CT, Alexandris N, et al. Nicotinic cholinergic system and COVID-19: In silico identification of interactions between α7 nicotinic acetylcholine receptor and the cryptic epitopes of SARS-Co-V and SARS-CoV-2 Spike glycoproteins. Food Chem Toxicol. 2021 Mar;149:112009. 

[12] Kumari P, Rothan H A, Natekar J P, et al. Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-hACE2 Mice. Viruses. 2021 Jan 19;13(1):132 

[13] Granon S, Faure P, Changeux JP. Executive and social behaviors under nicotinic receptor regulation. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9596-601. 

[14] Kessler P, Marchot P, Silva M, et al. The three‐finger toxin fold: a multifunctional structural scaffold able to modulate cholinergic functions. J Neurochem. 2017 Aug;142 Suppl 2:7-18

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