Comptes Rendus
Biologies
Jean-Pierre Changeux, Zahir Amoura, Felix A. Rey and Makoto
Miyara
A nicotinic hypothesis for Covid-19 with preventive and therapeutic
implications
Volume 343, issue 1 (2020), to appear.
<https://doi.org/10.5802/crbiol.8>
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Comptes Rendus
Biologies
2020, 343, n1, to appear
https://doi.org/10.5802/crbiol.8
News and events/ Actualités
A nicotinic hypothesis for Covid-19 with preventive
and therapeutic implications
Une hypothèse nicotinique pour Covid 19 et ses implications
préventives et thérapeutiques
Jean-Pierre Changeux ∗,a, Zahir Amoura b,c, Felix A. Reydand Makoto Miyarab,e
aInstitut Pasteur CNRS UMR 3571 Department of Neuroscience and Collège de
France, Paris France
bSorbonne Université, Inserm UMRS, Centre d’Immunologie et des Maladies
Infectieuses (CIMI-Paris)
cAssistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière,
Service de Médecine Interne 2, Maladies auto-immune et systémiques Institut E3M
dInstitut Pasteur, Structural Virology Unit, Department of Virology, CNRS UMR 3569,
Institut Pasteur Paris France
eAssistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière,
Département d’Immunologie, Paris, France.
E-mail: changeux@noos.fr.
Abstract. SARS-CoV-2 epidemics raises a considerable issue of public health at the planetary scale.
There is a pressing urgency to find treatments based upon currently available scientific knowledge.
Therefore, we tentatively propose a hypothesis which hopefully might ultimately help savelives. Based
on the current scientific literature and on new epidemiological data which reveal that currentsmoking
status appears to be a protective factor against the infection by SARS-CoV-2 [1], we hypothesize that
the nicotinic acetylcholine receptor (nAChR) plays a key role in the pathophysiology of Covid-19
infection and might represent a target for the prevention and control of Covid-19 infection.
Résumé. L’épidémie de SARS-Cov-2 pose un problème considérable de santé publique à l’échelle
planétaire. Il y a urgence extrême de découvrir des traitements qui se fondent sur les connaissances
scientifiques disponibles. Nous proposons donc une hypothèse plausible mais provisoire qui puisse le
moment venu contribuer à sauver des vies. Elle se fonde sur la littérature scientifique disponible et sur
des données épidémiologiques nouvelles qui révèlent que le statut de fumeur parait être un facteur
de protection contre l’infection par SARS-Cov-2 [1]. Nous proposons l’hypothèse que le récepteur
nicotinique de l’acétylcholine (nAChR) joue un rôle critique dans la pathophysiologie de l’infection
Covid-19 et puisse représenter une cible pour la prévention et le contrôle de l’infection.
Keywords. Covid-19, smoking, nicotinic receptors, clinical trials of nicotine patches.
Mots-clés. Covid-19, fumeurs, récepteurs nicotinique, essais clinique patch nicotine.
Manuscript received 16th April 2020, accepted 18th April 2020.
∗Corresponding author. Jean-Pierre Changeux and Zahir Amoura are equal first authors.
ISSN (electronic) : 1768-3238 https://comptes-rendus.academie- sciences.fr/biologies/
2Jean-Pierre Changeux et al.
Symptomatic Covid-19 disease (as caused by
SARS-CoV-2 virus) is observed in 2.5 percent of in-
fected individuals [2] indicating an individual vari-
ability in the clinical presentation. Among the epi-
demiological and clinical features of Covid-19, the
following features are of special interest for un-
derstanding the patho-physiolology, namely: (1) in
outpatients with favorable outcome : neurologi-
cal/psychiatric disorders, especially loss of sense of
smell which is specific of the disease and (2) in hos-
pitalized older patients with a poor prognosis : sys-
temic hyperinflammatory syndrome with increased
levels of circulating cytokines and atypical acute res-
piratory distress syndrome with loss of neurological
control of lung perfusion regulation and hypoxic
vasoconstriction [3]. This raises the issue of the basis
of inter-individual variability for the susceptibility to
infection.
The nAChR appears as a hypothetical clue for
the main clinical manifestations of Covid-19. It is
accepted that the angiotensin converting enzyme 2
(ACE2), represents the principal receptor molecule
for SARS-CoV-2 [4–6]. ACE2 is expressed at the tran-
scriptomic level in the lung, the small intestine and
colon, in the kidney, in the testis, in the heart mus-
cle and in the brain, yet the protein is not detected
in the lung [7]. In the brain, ACE2 is expressed in
both neurons and glia and particularly present in
the brain stem and in the regions responsible for
the regulation of cardiovascular functions, including
the subfornical organ, paraventricular nucleus, nu-
cleus of the tractus solitarius, and rostral ventrolat-
eral medulla [8]. Additional receptors or co-receptors
are, however, not excluded. The relationship between
nicotine and ACE2 has been explored in the frame-
work of cardiovascular and pulmonary diseases [9].
Accordingly, in the ACE/ANG II/AT1R arm, nicotine
increases the expression and/or activity of renin, ACE
and AT1R, whereas in the compensatory ACE2/ANG-
(1–7)/MasR arm, nicotine down regulates the expres-
sion and/or activity of ACE2 and AT2R, thus suggest-
ing a possible contribution of acetylcholine receptors
in ACE2 regulation. This possibility has not yet been
explored in the framework of viral neuroinfections.
There is strong evidence for a neurotropic action
of SARS-CoV-2 infection. It has been demonstrated
that β-coronaviruses to which the SARS-CoV-2 be-
longs, do not limit their presence to the respiratory
tract and have been shown to frequently invade the
CNS [10]. This propensity has been convincingly doc-
umented for the SARS-CoV-1, MERS-CoV and the
coronavirus responsible for porcine hemagglutinat-
ing encephalomyelitis (HEV 67N). In light of the high
similarity between SARS-CoV-1 and SARS-CoV-2, it is
quite likely that SARS-CoV-2 also possesses a similar
potential. Neuroinfection has been proposed to po-
tentially contribute to the pathophysiology and clin-
ical manifestations of Covid-19 [10] with the neu-
roinvasive potential of SARS-CoV-2 suggested to play
a role in the respiratory failure of Covid-19 patients
[11, 12]. Our nicotinic hypothesis proposes that the
virus could enter the body through neurons of the
olfactory system and/or through the lung leading to
different clinical features with different outcome, and
contrasts with the currently accepted view that ACE2
is the principal receptor of SARS-CoV-2 for its entry
into cells.
As mentioned, loss of sense of smell frequently
occurs in Covid-19 patients [13]. Furthermore, sev-
eral studies have reported that some patients in-
fected with SARS-CoV-2 show neurologic signs such
as headache (about 8 %), nausea and vomiting (1 %)
[11]. More recently, a study of 214 Covid-19 patients
[14] further found that about 88 % (78/88) of the se-
vere patients displayed neurologic manifestations in-
cluding acute cerebrovascular diseases and impaired
consciousness. Based on an epidemiological survey
on Covid-19, the median time from the first symp-
tom to dyspnea was 5.0 days, to hospital admission
was 7.0 days, and to the intensive care was 8.0 days
[15]. Therefore, the latency period may be adequate
for the virus to enter the nervous system, invade the
brain stem and affect the medullary neurons of the
respiratory centers. However, variability of the neuro-
logical signs was observed with patients having anos-
mia, showing in general a mild evolution without pul-
monary attack, in contrast with those without anos-
mia suggesting a diversity in the mode of prolifera-
tion and /or progression of the virus.
More than 20 years ago, Mohammed, Norrby &
Kristensson [16], in a pioneering study, showed with
a broad diversity of viruses (Poliovirus, Herpes sim-
plex virus, West Nile virus , Vesicular Stomatitis Virus,
influenza H1N1 virus [17]), that viruses enter the ol-
factory epithelium and progress first through the ol-
factory pathway in an anterograde direction and then
in a retrograde manner to the reticular neurons pro-
jecting to the olfactory bulbs, the median raphe neu-
C. R. Biologies,2020, 343, n1, to appear
Jean-Pierre Changeux et al. 3
rons (serotoninergic) and the ventral and horizontal
diagonal band (cholinergic) [16,18]. This olfactory in-
fection route scheme [18] has been recently extended
to Covid-19 infection [2, 11]. To further investigate
the molecular aspects of Covid-19 propagation in
the brain and its pharmacology, we have been aided
by abundant studies on rabies virus (RABV) a nega-
tive polarity, single-strand RNA virus that is distinct
from the coronaviruses [18–20]. nAChRs were shown
to be the first receptors for RABV [21]. Structural
studies further revealed that a short region in the
ectodomain of the rabies virus glycoprotein shows
sequence similarity to some snake toxins [20, 22]
that were initially used to isolate the nAChR from
fish electric organs [23]. These snake toxins [24] are
known to bind with high affinity and exquisite selec-
tivity to the peripheral muscle receptor, while also to
some brain receptors [25,26]. The neurotoxin-like re-
gion of the rabies virus glycoprotein inhibited acetyl-
choline responses of α4β2 nAChRs in vitro, as did
the full length ectodomain of the rabies virus gly-
coprotein [20]. The same peptides significantly al-
tered a nAChR elicited behaviour in C. elegans and in-
creased locomotor activity levels when injected into
the CNS of mice [20]. The nAChR thus plays a criti-
cal role in the host-pathogen interaction in the case
of the RABV. Furthermore, a broad variety of nAChR
oligomers are distributed throughout the brain, in-
cluding the reticular core neurons and the spinal
cord, with the α4β2 and α7 nAChR oligomers being
the most frequent [27]. The hypothesis we wish to ex-
plore is to what implications these data may hold for
SARS-CoV-2 infection and we suggest a strong role of
nAChR in the disorder.
The nAChR pathway is hypothesized to be en-
gaged in the Covid-19 inflammatory syndrome.
The nervous system, through the vagus nerve,
can significantly and rapidly inhibit the release of
macrophage TNF, and attenuate systemic inflam-
matory responses [28]. This physiological mech-
anism, termed the ‘cholinergic anti-inflammatory
pathway’ has major implications in immunology
and in therapeutics. The cytokine production of
macrophages—one of the main cell types found
in the bronchoalveolar fluid—is under the phys-
iological control of auto/paracrine acetylcholine
through their nAChRs [29]. Following dysregulation
of macrophage nAChRs, the profile of cytokines
massively secreted include Il1, Il6, TNF et Il18. This
cytokine profile shows striking analogies with the
cytokine storm syndrome, leading to the hyper-
inflammatory syndrome described in a subgroup
of Covid-19 patients [30]. Systemic coagulopathy
with venous and arterial thrombosis is one of the
critical aspects of the morbidity and mortality of
Covid-19. In line with our hypothesis, one should
note that hematopoietic α7-nAChR defficiency in-
creases platelet reactive status, which could explain
the thrombogenic presentation of Covid-19 [31]. Al-
though selective cytokine blockers (eg, IL1-receptor
antagonist anakinra or anti-IL6 tocilizumab) have
been proposed for the control of Covid-19 cytokine
storm, their efficacy is still to be explored. Interest-
ingly, α7 agonists, including nicotine, have proven
to be effective in reducing macrophage cytokine
production and inflammation in animal models of
pancreatitis [32] and peritonitis [33]. In this setting,
a nicotinic treatment that might possibly antago-
nize the blocking action of SARS-CoV-2 on the AChR
through a possible modulation of the ACE2 – nAChR
interaction, would act earlier than anti-cytokine
therapies. nAChR modulation by Covid-19 might
tentatively account for the hyperinflammatory fea-
tures observed in a subgroup of Covid-19 patients,
mimicking bona fide the macrophage activation
syndrome.
Of note, our hypothesis could explain the high
prevalence of obesity and diabetes mellitus observed
in severe forms of Covid19. The diminished vagus
nerve activity previously described in these two ill-
nesses could be potentiated by the Covid-19 elicited
nicotinic receptor dysregulation, leading to a hyper-
inflammatory state often reported in obese patients
[29].
nAChRs are present in the lung epithelium. The
non-neuronal cholinergic system contributes to the
regulation of cell functions such as cell-cell interac-
tion, apoptosis, and proliferation and it is well estab-
lished that human bronchial epithelial cells contain
nAChRs. The airway epithelium expresses α3, α4, α5,
α7, α9, β2, and β4-nAChRs subunits [34–37] and
their contribution has been discussed in the frame-
work of airway epithelial basal cell proliferation-
differentiation and their alteration in lung cancers
[38]. These nAChRs are mentioned here as possi-
ble targets of Covid-19 infection of the lung, which
would take place concomitantly with, and/or as a
consequence of, the neuro-infection. Additionally,
C. R. Biologies,2020, 343, n1, to appear
4Jean-Pierre Changeux et al.
nAChRs are involved in lung perfusion regulation,
which seems to be disrupted in the atypical acute res-
piratory distress syndrome reported in Covid-19 pa-
tients [3].
A potential protective effect of smoking and of
nicotine on SARS-CoV-2 infection has been noted.
Until recently [39], no firm conclusions could be
drawn from studies evaluating the rates of current
smokers in Covid-19. All these studies [40–48], al-
though reporting low rates of current smokers, rang-
ing from 1.4 % to 12.5 %, did not take into account
the main potential confounders of smoking includ-
ing age and sex. In the study that two of us are re-
porting [1], the rates of current smoking remain be-
low 5 % even when main confounders for tobacco
consumption, i.e. age and sex, in- or outpatient sta-
tus, were considered. Compared to the French gen-
eral population, the Covid-19 population exhibited
a significantly weaker current daily smoker rate by
80.3 % for outpatients and by 75.4 % for inpatients.
Thus, current smoking status appears to be a protec-
tive factor against the infection by SARS-CoV-2. Al-
though the chemistry of tobacco smoke is complex,
these data are consistent with the hypothesis that its
protective role takes place through direct action on
various types of nAChRs expressed in neurons, im-
mune cells (including macrophages), cardiac tissue,
lungs, and blood vessels.
Mechanisms engaged in Covid-19 as nAChR
disease might be tentatively suggested. There is
structural evidence supporting the hypothesis that
SARS-CoV-2 virus is a nicotinic agent. The recently
reported X-ray structure of the RABV glycoprotein (G)
ectodomain [49] shows that the region correspond-
ing to the neurotoxin-like peptide is exposed at the G
surface, in agreement with the fact that this region is
part of the major antigenic region II of RABV [50]. The
recently published cryo-EM structure of the trimeric
SARS-CoV-2 spike (S) protein [51, 52] revealed an
insertion with respect to that of SARS-CoV-1, in a
loop that is disordered in the reported structure, and
which has a polybasic sequence that corresponds
to a furin site. Importantly, this exposed loop of the
SARS-CoV-2 S protein also contains a motif that is
homologous to that of snake neurotoxins and to
the RABV neurotoxin-like region (Figure 1). This ob-
servation supports the hypothesis that SARS-CoV-2
virus itself is a nAChR blocker.
Figure 1. The neurotoxin motifs. Amino acid
sequence alignment of the motifs found in tox-
ins from snakes of the Ophiophagus (cobra)
and Bungarus genera, in G from three RABV
strains and in S from SARS-CoV-2.
Nicotine may be suggested as a potential preven-
tive agent against Covid-19 infection. Both the epi-
demiological/clinical evidence and the in silico find-
ings may suggest that Covid-19 infection is a nAChR
disease that could be prevented and may be con-
trolled by nicotine. Nicotine would then sterically
or allosterically compete with the SARS-CoV-2 bind-
ing to the nAChR. This legitimates the use of nico-
tine as a protective agent against SARS-CoV-2 infec-
tion and the subsequent deficits it causes in the CNS.
Thus, in order to prevent the infection and the retro-
propagation of the virus through the CNS, we plan
a therapeutic assay against Covid-19 with nicotine
(and other nicotinic agents) patches or other delivery
methods (like sniffing/chewing) in hospitalized pa-
tients and in the general population.
In conclusion, we propose, and try to justify, the
hypothesis that nAChRs play a critical role in the
pathophysiology of SARS-CoV-2 infection and as a
consequence propose nicotine and nicotinic orthos-
teric and/or allosteric agents as a possible therapy
for SARS-CoV-2 infection. Interestingly, ivermectin,
which has been recently shown to inhibit the replica-
tion of SARS-CoV-2 in cells in vitro [53], is a positive
allosteric modulator of α7 nAChR [54]. The nicotinic
hypothesis might be further challenged by additional
clinical studies and by experimental observations de-
termining whether SARS-CoV-2 physically interacts
with the nAChR in vitro, for instance by electrophys-
iological recordings, high resolution EM and by ani-
mal model studies. Further work should also specify
the still enigmatic relationships between ACE2 and
nAChRs in the nervous system.
One should not forget that nicotine is a drug of
abuse [55] responsible for smoking addiction. Smok-
C. R. Biologies,2020, 343, n1, to appear
Jean-Pierre Changeux et al. 5
ing has severe pathological consequences and re-
mains a serious danger for health. Yet under con-
trolled settings, nicotinic agents could provide an
efficient treatment for an acute infection such as
Covid-19.
Acknowledgments
We would like to specially thank Pr. Serge Haroche
for establishing the contact between JPC and ZA.
We thank Dr. Pablo Guardado Calvo (Institut Pas-
teur, Paris) for the amino acid sequence analysis of
the neurotoxin motif, Pr. Florence Tubach for fruit-
ful discussions, Pr. Gérard Orth for valuable support
and discussions, Pr. Daniel Louvard and Pr. Henri
Korn for encouragements. JPC acknowledges useful
exchanges with Dr. Abdul Mohammed and Dr. Kister
Kristensson at early stages of the reflection and the
Pasteur Institute shared discussions network orga-
nized by the Neuroscience Department and its for-
mer Chairman Pr. PM Lledo. We thank Dr. Kurt Sailor
for carefully editing the text.
Competing financial interests
The authors declare no competing financial interests.
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