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A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications

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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 save lives. Based on the current scientific literature and on new epidemiological data which reveal that current smoking 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.
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>
© Académie des sciences, Paris and the authors, 2020.
Some rights reserved.
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CRE ATIV E COMMONS ATTR IB UT IO N 4.0 IN TE RNATIONAL LI CE NS E.
http://creativecommons.org/licenses/by/4.0/
Les Comptes Rendus. Biologies sont membres du
Centre Mersenne pour l’édition scientifique ouverte
www.centre-mersenne.org
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
dierent clinical features with dierent 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 aect 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 anity 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 deciency 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 ecacy is still to be explored. Interest-
ingly, α7 agonists, including nicotine, have proven
to be eective 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-
dierentiation 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 eect 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 sning/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
ecient 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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... 37 38 These findings prompted an editorial 39 and the registration of clinical trials testing the hypothesis that nicotine may prevent infection and progression of COVID-19. 40 While the clinical trials have not yet concluded, research conducted since does not support any therapeutic or prophylactic benefits of nicotine on COVID-19. 40 In fact, in addition to smoking increasing odds of disease progression and severe symptoms, 41-43 a recent systematic review strongly suggests that nicotine, including ECs and smokeless products, are a likely risk factor for infection and progression of COVID-19. ...
... 40 While the clinical trials have not yet concluded, research conducted since does not support any therapeutic or prophylactic benefits of nicotine on COVID-19. 40 In fact, in addition to smoking increasing odds of disease progression and severe symptoms, 41-43 a recent systematic review strongly suggests that nicotine, including ECs and smokeless products, are a likely risk factor for infection and progression of COVID-19. 44 Although more research is needed to make definitive claims about the effects of nicotine, there is currently no evidence supporting a therapeutic use for nicotine with respect to COVID-19. ...
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Objective To examine the role of social media in promoting recall and belief of distorted science about nicotine and COVID-19 and whether recall and belief predict tobacco industry beliefs. Design Young adults aged 18–34 years (N = 1225) were surveyed cross-sectionally via online Qualtrics panel. The survey assessed recall and belief in three claims about nicotine and COVID-19 and three about nicotine in general followed by assessments of industry beliefs and use of social media. Ordinal logistic regression with robust standard errors controlling for gender, race/ethnicity, education, current e-cigarette use and age was used to examine relationships between variables. Results Twitter use was associated with higher odds of recall (OR=1.21, 95% CI=1.01 to 1.44) and belief (OR=1.26, 95% CI=1.04 to 1.52) in COVID-19-specific distorted science. YouTube use was associated with higher odds of believing COVID-19-specific distorted science (OR=1.32, 95% CI=1.09 to 1.60). Reddit use was associated with lower odds of believing COVID-19-specific distorted science (OR=0.72, 95% CI=0.59 to 0.88). Recall (OR=1.26, 95% CI=1.07 to 1.47) and belief (OR=1.28, 95% CI=1.09 to 1.50) in distorted science about nicotine in general as well as belief in distorted science specific to COVID-19 (OR=1.61, 95% CI=1.34 to 1.95) were associated with more positive beliefs about the tobacco industry. Belief in distorted science about nicotine in general was also associated with more negative beliefs about the tobacco industry (OR=1.18, 95% CI=1.02 to 1.35). Conclusions Use of social media platforms may help to both spread and dispel distorted science about nicotine. Addressing distorted science about nicotine is important, as it appears to be associated with more favourable views of the tobacco industry which may erode public support for effective regulation.
... An increasing number of studies have reported this reduced risk of SARS-CoV-2 infection in current smokers in different contexts (cross-sectional studies in the general population; cross-sectional, case-control or control studies in different populations) [19][20][21][22][23][24] . Our results from a large multicenter prospective study in a young population of HCWs with 26.9% current smokers support the role of use of tobacco substances as protective against SARS-CoV-2 infection, which may act through the nicotine pathway [25][26][27][28] . This result should not encourage smoking to limit the risk of COVID-19; indeed, 78,000 deaths per year are due to smoking in France 29 . ...
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With the COVID-19 pandemic, documenting whether health care workers (HCWs) are at increased risk of SARS-CoV-2 contamination and identifying risk factors is of major concern. In this multicenter prospective cohort study, HCWs from frontline departments were included in March and April 2020 and followed for 3 months. SARS-CoV-2 serology was performed at month 0 (M0), M1, and M3 and RT-PCR in case of symptoms. The primary outcome was laboratory-confirmed SARS-CoV-2 infection at M3. Risk factors of laboratory-confirmed SARS-CoV-2 infection at M3 were identified by multivariate logistic regression. Among 1062 HCWs (median [interquartile range] age, 33 [28–42] years; 758 [71.4%] women; 321 [30.2%] physicians), the cumulative incidence of SARS-CoV-2 infection at M3 was 14.6% (95% confidence interval [CI] [12.5; 16.9]). Risk factors were the working department specialty, with increased risk for intensive care units (odds ratio 1.80, 95% CI [0.38; 8.58]), emergency departments (3.91 [0.83; 18.43]) and infectious diseases departments (4.22 [0.92; 18.28]); current smoking was associated with reduced risk (0.36 [0.21; 0.63]). Age, sex, professional category, number of years of experience in the job or department, and public transportation use were not significantly associated with laboratory-confirmed SARS-CoV-2 infection at M3. The rate of SARS-CoV-2 infection in frontline HCWs was 14.6% at the end of the first COVID-19 wave in Paris and occurred mainly early. The study argues for an origin of professional in addition to private life contamination and therefore including HCWs in the first-line vaccination target population. It also highlights that smokers were at lower risk. Trial registration The study has been registered on ClinicalTrials.gov: NCT04304690 first registered on 11/03/2020.
... When targeted proteins are vital, pathogenicity may be greater than that due to viral replication. RNA viruses reproduce their capsid proteins in host cells and duplicate their genome leaving behind RNA fragments, which can behave like miRs in the host genome, if they bind to Argonaut proteins facilitating hybridization to mRNA and then its hydrolysis [50][51][52][53][54][55][56][57][58]. ...
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The end of the acute phase of the COVID-19 pandemic is near in some countries as declared by World Health Organization (WHO) in January 2022 based on some studies in Europe and South Africa despite unequal distribution of vaccines to combat the disease spread globally. The heterogeneity in individual age and the reaction to biological and environmental changes that has been observed in COVID-19 dynamics in terms of different reaction to vaccination by age group, severity of infection per age group, hospitalization and Intensive Care Unit (ICU) records show different patterns, and hence, it is important to improve mathematical models for COVID-19 pandemic prediction to account for different proportions of ages in the population, which is a major factor in epidemic history. We aim in this paper to estimate, using the Usher model, the lifespan loss due to viral infection and ageing which could result in pathological events such as infectious diseases. Exploiting epidemiology and demographic data firstly from Cameroon and then from some other countries, we described the ageing in the COVID-19 outbreak in human populations and performed a graphical representation of the proportion of sensitivity of some of the model parameters which we varied. The result shows a coherence between the orders of magnitude of the calculated and observed incidence numbers during the epidemic wave, which constitutes a semi-quantitative validation of the mathematical modelling approach at the population level. To conclude, the age heterogeneity of the populations involved in the COVID-19 outbreak needs the consideration of models in age groups with specific susceptibilities to infection.
... One hypothesis is that nicotine decreases the expression of the angiotensin converting enzyme 2 (ACE 2) which is a receptor of SARS-CoV-2. Another hypothesis is that SARS-CoV-2 and nicotine compete for binding to the nicotine acetylcholine receptor (nAChR) which is possibly involved in the physiopathology of COVID-19 infection [53]. However, our results should be interpreted with caution as we conducted an observational study. ...
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Seroprevalence studies are essential to get an accurate estimate of the actual SARS-CoV-2 diffusion within populations. We report on the findings of the first serosurvey conducted in Tunis prior to the implementation of mass vaccination and analyzed factors associated with seropositivity. A household cross sectional survey was conducted (March–April 2021) in Tunis, spanning the end of the second wave and the beginning of the third wave of COVID-19. SARS-CoV-2 specific immunoglobulin G (IgG) antibodies to the spike (S-RBD) or the nucleocapsid (N) proteins were detected by in-house ELISA tests. The survey included 1676 individuals from 431 households. The mean age and sex ratio were 43.3 ± 20.9 years and 0.6, respectively. The weighted seroprevalence of anti-N and/or anti-S-RBD IgG antibodies was equal to 38.0% (34.6–41.5). In multivariate analysis, age under 10, no tobacco use, previous diagnosis of COVID-19, a history of COVID-19 related symptoms and contact with a COVID-19 case within the household, were independently associated with higher SARS-CoV-2 seroprevalence. More than one third of people living in Tunis obtained antibodies to SARS-CoV-2. Further studies are needed to monitor changes in these figures as Tunisian population is confronted to the subsequent epidemic waves and to guide the vaccine strategy.
... The association might, for example, be explained by a role of the nicotinic acetylcholine receptor (nAChR). 19 Because other viruses, such as rabies virus, have been known to bind nAChRs, it was hypothesised recently that SARS-CoV-2 spike protein might bind nAChRs as a coreceptor for infection. 20 21 Indeed, in silico molecular docking simulations predicted binding of spike to nAChRs. ...
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Objectives: The first German SARS-CoV-2 outbreak was a superspreading event in Gangelt, North Rhine-Westphalia, during indoor carnival festivities called 'Kappensitzung' (15 February 2020). We determined SARS-CoV-2 RT-PCR positivity rate, SARS-CoV-2-specific antibodies, and analysed the conditions and dynamics of superspreading, including ventilation, setting dimensions, distance from infected persons and behavioural patterns. Design: In a cross-sectional epidemiological study (51 days postevent), participants were asked to give blood, pharyngeal swabs and complete self-administered questionnaires. Setting: The SARS-CoV-2 superspreading event took place during festivities in the small community of Gangelt in February 2020. This 5-hour event included 450 people (6-79 years of age) in a building of 27 m × 13.20 m × 4.20 m. Participants: Out of 450 event participants, 411 volunteered to participate in this study. Primary and secondary outcome measures: Primary outcome: infection status (determined by IgG ELISA). Secondary outcome: symptoms (determined by questionnaire). Results: Overall, 46% (n=186/404) of participants had been infected, and their spatial distribution was associated with proximity to the ventilation system (OR 1.39, 95% CI 0.86 to 2.25). Risk of infection was highly associated with age: children (OR 0.33, 95% CI 0.267 to 0.414) and young adults (age 18-25 years) had a lower risk of infection than older participants (average risk increase of 28% per 10 years). Behavioural differences were also risk associated including time spent outside (OR 0.55, (95% CI 0.33 to 0.91) or smoking (OR 0.32, 95% CI 0.124 to 0.81). Conclusions: Our findings underline the importance of proper indoor ventilation for future events. Lower susceptibility of children/young adults indicates their limited involvement in superspreading.
... An imbalanced inflammatory response is responsible for tissue damage and COVID-19 severity [145]. The cholinergic system has been proposed as one of the regulators of COVID-19 induced hypercytokinemia [146][147][148][149][150]. CHRFAM7A expression showed a slight tendency to decrease its level in a cohort of SARS-CoV-2 patients compared with healthy controls [14]. ...
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CHRFAM7A is a relatively recent and exclusively human gene arising from the partial duplication of exons 5 to 10 of the α7 neuronal nicotinic acetylcholine receptor subunit (α7 nAChR) encoding gene, CHRNA7. CHRNA7 is related to several disorders that involve cognitive deficits, including neuropsychiatric, neurodegenerative, and inflammatory disorders. In extra-neuronal tissues, α7nAChR plays an important role in proliferation, differentiation, migration, adhesion, cell contact, apoptosis, angiogenesis, and tumor progression, as well as in the modulation of the inflammatory response through the “cholinergic anti-inflammatory pathway”. CHRFAM7A translates the dupα7 protein in a multitude of cell lines and heterologous systems, while maintaining processing and trafficking that are very similar to the full-length form. It does not form functional ion channel receptors alone. In the presence of CHRNA7 gene products, dupα7 can assemble and form heteromeric receptors that, in order to be functional, should include at least two α7 subunits to form the agonist binding site. When incorporated into the receptor, in vitro and in vivo data showed that dupα7 negatively modulated α7 activity, probably due to a reduction in the number of ACh binding sites. Very recent data in the literature report that the presence of the duplicated gene may be responsible for the translational gap in several human diseases. Here, we will review the studies that have been conducted on CHRFAM7A in different pathologies, with the intent of providing evidence regarding when and how the expression of this duplicated gene may be beneficial or detrimental in the pathogenesis, and eventually in the therapeutic response, to CHRNA7-related neurological and non-neurological diseases.
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The use of electronic cigarettes (e-cigarette) and vaping devices started as a potential aid for cessation and reducing the harmful consequences of cigarette smoking, mainly in the adult population. Today e-cigarette use is highly increasing in vulnerable populations, especially young and pregnant women, due to the misconception of its harmless use. Despite the growing acknowledgment in e-cigarette as a potential harmful device, and due to mixed information found concerning its beneficial aid for smokers, along with an insufficient clinical study done in human models, it is important to further evaluate the possible benefits and risks of non-combusting, vaping nicotine or non-nicotine delivery devices. In this review we tried to summarize the latest updated information found in the literature, concentrating mainly in the variety of adverse effects of e-cigarette use and its contribution for recent and future health concerns.
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Purpose: Epidemiologic studies have documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia. Methods: In this multicentre, double-blind, placebo-controlled trial conducted in 18 intensive care units in France, we randomly assigned adult patients (non-smokers, non-vapers or who had quit smoking/vaping for at least 12 months) with proven COVID-19 pneumonia receiving invasive mechanical ventilation for up to 72 h to receive transdermal patches containing either nicotine at a daily dose of 14 mg or placebo until 48 h following successful weaning from mechanical ventilation or for a maximum of 30 days, followed by 3-week dose tapering by 3.5 mg per week. Randomization was stratified by centre, non- or former smoker status and Sequential Organ Function Assessment score (< or ≥ 7). The primary outcome was day-28 mortality. Main prespecified secondary outcomes included 60-day mortality, time to successful extubation, days alive and free from mechanical ventilation, renal replacement therapy, vasopressor support or organ failure at day 28. Results: Between November 6th 2020, and April 2nd 2021, 220 patients were randomized from 18 active recruiting centers. After excluding 2 patients who withdrew consent, 218 patients (152 [70%] men) were included in the analysis: 106 patients to the nicotine group and 112 to the placebo group. Day-28 mortality did not differ between the two groups (30 [28%] of 106 patients in the nicotine group vs 31 [28%] of 112 patients in the placebo group; odds ratio 1.03 [95% confidence interval, CI 0.57-1.87]; p = 0.46). The median number of day-28 ventilator-free days was 0 (IQR 0-14) in the nicotine group and 0 (0-13) in the placebo group (with a difference estimate between the medians of 0 [95% CI -3-7]). Adverse events likely related to nicotine were rare (3%) and similar between the two groups. Conclusion: In patients having developed severe COVID-19 pneumonia requiring invasive mechanical ventilation, transdermal nicotine did not significantly reduce day-28 mortality. There is no indication to use nicotine in this situation.
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Some clinical studies have indicated activity of ivermectin, a macrocyclic lactone, against COVID-19, but a biological mechanism initially proposed for this anti-viral effect is not applicable at physiological concentrations. This in silico investigation explores potential modes of action of ivermectin and 14 related compounds, by which the infectivity and morbidity of the SARS-CoV-2 virus may be limited. Binding affinity computations were performed for these agents on several docking sites each for models of (1) the spike glycoprotein of the virus, (2) the CD147 receptor, which has been identified as a secondary attachment point for the virus, and (3) the alpha-7 nicotinic acetylcholine receptor (α7nAChr), an indicated point of viral penetration of neuronal tissue as well as an activation site for the cholinergic anti-inflammatory pathway controlled by the vagus nerve. Binding affinities were calculated for these multiple docking sites and binding modes of each compound. Our results indicate the high affinity of ivermectin, and even higher affinities for some of the other compounds evaluated, for all three of these molecular targets. These results suggest biological mechanisms by which ivermectin may limit the infectivity and morbidity of the SARS-CoV-2 virus and stimulate an α7nAChr-mediated anti-inflammatory pathway that could limit cytokine production by immune cells.
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The international spread of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) poses a global challenge on both healthcare and society. A multitude of research efforts worldwide aim at characterizing the cellular factors involved in viral transmission in order to reveal therapeutic targets. For a full understanding of the susceptibility for SARS-CoV-2 infection, the cell type-specific expression of the host cell surface receptor is necessary. The key protein suggested to be involved in host cell entry is Angiotensin I converting enzyme 2 (ACE2), and its expression has been reported in various human organs, in some cases with inconsistent or contradictory results. Here, we aim to verify a reliable expression profile of ACE2 in all major human tissues and cell types. Based on stringently validated immunohistochemical analysis and high-throughput mRNA sequencing from several datasets, we found that ACE2 expression is mainly localized to microvilli of the intestinal tract and renal proximal tubules, gallbladder epithelium, testicular Sertoli cells and Leydig cells, glandular cells of seminal vesicle and cardiomyocytes. The expression in several other previously reported locations, including alveolar type II (AT2) cells, could not be confirmed. Furthermore, ACE2 expression was absent in the AT2 lung carcinoma cell line A549, often used as a model for viral replication studies. Our analysis suggests that the expression of ACE2 in the human respiratory system appears to be limited, and the expression of the receptor in lung or respiratory epithelia on the protein level is yet to be confirmed. This raises questions regarding the role of ACE2 for infection of human lungs and highlights the need to further explore the route of transmission during SARS-CoV-2 infection.
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Background: The amelioration of the current COVID pandemic relies on swift and efficient case finding as well as stringent social distancing measures. Current advice suggests that fever or new onset dry cough are the commonest presenting complaints. Methodology: We present a case report and case series as well as other evidence that there is an important fourth presenting syndrome, namely isolated sudden onset anosmia (ISOA), which should be considered highly suspicious for SARS-CoV-2. Results: A patient presenting with ISOA who went on to test positive for infection with COVID-19 and did not develop any further symptoms as well as a case series of similar patients although limited by the lack of reliable testing at the moment. Conclusions: We posit the existence of a fourth common syndrome of COVID-19 infection: isolated sudden onset anosmia (ISOA) and urge the international community to consider this presentation in current management advice.
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Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 hours post infection with SARS-CoV-2 able to effect ∼5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
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A novel and highly pathogenic coronavirus (SARS-CoV-2) has caused an outbreak in Wuhan city, Hubei province of China since December 2019, and soon spread nationwide and spilled over to other countries around the world1–3. To better understand the initial step of infection at an atomic level, we determined the crystal structure of the SARS-CoV-2 spike receptor-binding domain (RBD) bound to the cell receptor ACE2 at 2.45 Å resolution. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also utilizes ACE2 as the cell receptor⁴. Structural analysis identified residues in the SARS-CoV-2 RBD that are critical for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly argue for convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses1–3,5. The epitopes of two SARS-CoV antibodies targeting the RBD are also analysed with the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.
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The new coronavirus, classified as SARS‐CoV‐2 that emerged in Hubei province in China, causes a new coronavirus disease, which was termed COVID‐19 by WHO on February 11, 2020. COVID‐19 claimed almost 19000 lives around the world by March 25, 2020
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The outbreak of the novel coronavirus in China (SARS-CoV-2) that began in December 2019 presents a significant and urgent threat to global health. This study was conducted to provide the international community with a deeper understanding of this new infectious disease. Epidemiological, clinical features, laboratory findings, radiological characteristics, treatment, and clinical outcomes of 135 patients in northeast Chongqing were collected and analyzed in this study. A total of 135 hospitalized patients with COVID-19 were enrolled. The median age was 47 years (interquartile range, 36-55), and there was no significant gender difference (53.3% men). The majority of patients had contact with people from the Wuhan area. Forty-three (31.9%) patients had underlying disease, primarily hypertension (13 [9.6%]), diabetes (12 [8.9%]), cardiovascular disease (7 [5.2%]), and malignancy (4 [3.0%]). Common symptoms included fever (120 [88.9%]), cough (102 [76.5%]), and fatigue (44 [32.5%]). Chest computed tomography scans showed bilateral patchy shadows or ground glass opacity in the lungs of all the patients. All patients received antiviral therapy (135 [100%]) (Kaletra and interferon were both used), antibacterial therapy (59 [43.7%]), and corticosteroids (36 [26.7%]). In addition, many patients received traditional Chinese medicine (TCM) (124 [91.8%]). It is suggested that patients should receive Kaletra early and should be treated by a combination of Western and Chinese medicines. Compared to the mild cases, the severe ones had lower lymphocyte counts and higher plasma levels of Pt, APTT, d-dimer, lactate dehydrogenase, PCT, ALB, C-reactive protein, and aspartate aminotransferase. This study demonstrates the clinic features and therapies of 135 COVID-19 patients. Kaletra and TCM played an important role in the treatment of the viral pneumonia. Further studies are required to explore the role of Kaletra and TCM in the treatment of COVID-19.
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Background: Since December 2019, an outbreak of Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, and is now becoming a global threat. We aimed to delineate and compare the immunologic features of severe and moderate COVID-19. Methods: In this retrospective study, the clinical and immunologic characteristics of 21 patients (17 male and 4 female) with COVID-19 were analyzed. These patients were classified as severe (11 cases) and moderate (10 cases) according to the Guidelines released by the National Health Commission of China. Results: The median age of severe and moderate cases was 61.0 and 52.0 years, respectively. Common clinical manifestations included fever, cough and fatigue. Compared to moderate cases, severe cases more frequently had dyspnea, lymphopenia, and hypoalbuminemia, with higher levels of alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin and D-dimer as well as markedly higher levels of IL-2R, IL-6, IL-10, and TNF-α. Absolute number of T lymphocytes, CD4+T and CD8+T cells decreased in nearly all the patients, and were markedly lower in severe cases (294.0, 177.5 and 89.0 × 106/L) than moderate cases (640.5, 381.5 and 254.0 × 106/L). The expressions of IFN-γ by CD4+T cells tended to be lower in severe cases (14.1%) than moderate cases (22.8%). Conclusion: The SARS-CoV-2 infection may affect primarily T lymphocytes particularly CD4+T and CD8+ T cells, resulting in decrease in numbers as well as IFN-γ production. These potential immunological markers may be of importance due to their correlation with disease severity in COVID-19.
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