ArticlePDF Available
Infectious Disorders – Drug Targets
ISSN: 1871-5265
eISSN: 2212-3989
SCIENCE
BENTHAM
Infectious Disorders
Drug Targets
2212-3989/23 $65.00+.00 © 2023 Bentham Science Publishers
26
Ziad Fajloun1,2, Christian Legros3 and Jean-Marc Sabatier4,*
1
Department of Biology, Faculty of Sciences 3, Lebanese University, Campus Michel Slayman Ras Maska, Tripoli
1352, Lebanon;
2
Laboratory of Applied Biotechnology (LBA3B), Azm Center for Research in Biotechnology and
its Applications, EDST, Lebanese University, Tripoli 1300, Lebanon;
3
College of Life Sciences, University of
Angers, INSERM, CNRS, MITOVASC, Team 2 CarMe, SFR ICAT, Angers 49000, France
;
4
College of Life Sciences,
Aix-Marseille University
, CNRS, INP, Inst Neurophysiopathol, Marseille 13385, France
1. INTRODUCTION
Ehlers-Danlos syndrome (EDS) is a rare hereditary pathology of the connective tissue,
with an average incidence (variable according to the 14 types of EDS) of 1 person in 5000
[1]. Over the past few months, we have had numerous contacts with people suffering from
long Covid (thanks to Drs. Claude Escarguel (UPGCS), Jean-Roch Gonet and Christine Cot-
ton), and we have noticed a very high proportion of people (previously infected with SARS-
CoV-2 and/or "vaccinated" against Covid-19) with established EDS to have the most serious and disabling forms of
long COVID. It has thus become obvious to us that the pre-existence of EDS in a person confers a high-risk factor for a
very severe COVID-19 or long COVID [2-5].
The preliminary diagnosis of EDS is made on the basis of family elements due to hereditary transmission and specif-
ic clinical signs (hyperlaxity and/or joint pain, cutaneous hyperextensibility, thinness and transparency of the skin, ab-
normal presence of hematomas, visible veins, healing problems, propensity for sprains and dislocations, the fragility of
connective tissues, postural disorders and scoliosis, digestive and/or vascular disorders, extreme fatigability, etc.) of the
person concerned [6]. Genetic confirmation (e.g., mutation(s) of the COL3A1 gene) is then carried out in specialized
medical centers, with the exception of hyper-mobile EDS (type of EDS) because the genetic bases of this EDS remain
unknown to date. In the case of potential EDS of the vascular type, a vascular assessment is ordered (CT angiography,
echography of the heart, echo Doppler of the arteries) [7].
EDS is a set of genetic pathologies causing abnormalities in the connective tissue of intercellular support, ensuring
the cohesion and maintenance of tissues and organs. These result in various "mechanical" particularities in people suf-
fering from EDS, such as hyper-elasticity of the skin, tendons, ligaments and muscles surrounding the joints (hypermo-
bility of the joints), as well as fragility and abnormal vascular system (blood vessels). Thus, EDS is characterized by
skin and joint hyperlaxity due to excessive elasticity of the connective tissue [1, 6].
People with EDS can thus present chronic joint and muscle pain, accompanied by exacerbated fragility to sprains and
dislocations. It is a genetic disease mainly affecting the production of collagen, one of the extracellular matrix proteins.
Complications can be varied, including early arthritis, osteoporosis, healing difficulties, and others. The prevalence of
EDS is approximately one in five thousand people (both men and women), making it a rare condition. A deficiency in
the production of collagen (or even other molecule(s) of the extracellular matrix) is at the center of EDS [1, 8]. It is an
important protein because collagen is ubiquitous in the body (skin, ligaments, tendons, cartilage, bones, and various
connective tissues - about 80% of our body - including the pulmonary interstitium) and represents more than 30% of the
total proteins of the human body. There are several types of collagen depending on the organs and tissues: type I colla-
gen (present in the skin, ligaments, tendons, and bone tissue), type II collagen (present in cartilage), and type III colla-
gen (found in the vascular system and muscles). EDS is polymorphic, and several variants of this syndrome have been
described and have been classified into 13 types whose prevalence is highly variable (hyper-mobile, vascular, classic
types, etc.) [8].
The extracellular matrix, which constitutes a "cement" of adhesion between the cells of the various tissues of our
organism, is composed of an assembly of numerous molecules, of which the main are proteins/glycoproteins, proteogly-
cans (specific glycoproteins), glycosaminoglycans (polysaccharides), growth factors and others. Among these mole-
cules, the major adhesion proteins or glycoproteins of the extracellular matrix are collagen (deficient in people with
*Address correspondence to this author at College of Life Sciences, Aix-Marseille University, CNRS, INP, Inst Neurophysiopathol, Marseille 13385, France;
Tel: ++33 6 40 15 24 19; E-mail: sabatier.jm1@gmail.com
A R T I C L E H I S T O R Y!
Received: December 14, 2022
Accepted: December 21, 2022
DOI:
10.2174/1871526523666230104145108!
Send Orders for Reprints to reprints@benthamscience.net
Infectious Disorders - Drug Targets, 2023, 23, e040123212375
EDITORIAL
COVID-19 and Ehlers-Danlos Syndrome: The Dangers of the Spike
Protein of SARS-CoV-2
COVID-19 and Ehlers-Danlos Syndrome e040123212375 Infectious Disorders - Drug Targets, 2023, Vol. 23, No. 3
27
EDS), laminin, fibronectin, and vitronectin. These molecules can interact with transmembrane receptors called "integ-
rins" present on the surface of cells. Thus, integrins are involved in cell adhesion by interacting with pro-
teins/glycoproteins of the extracellular matrix (via the extracellular part of the integrin) and the cytoskeleton of the cell
(via the intracellular part of the integrin) [9]. These extracellular matrix proteins/glycoproteins share one (or more) RGD
(Arg-Gly-Asp) motif(s), which allow(s) their interactions with some of the integrins of our cells. To simplify, if we con-
sider that these molecules of the extracellular matrix are necklaces of pearls (each pearl being an amino acid residue,
such as R, G or D), these molecules have one (or more) sequence(s) identical(s) of three successive beads (that is to say
the RGD beads) in the collar allowing attachment to these integrins. In the case of collagen (collagen I), which mainly
forms a helical triple helix structure, the RGD motifs are “hidden” (known as cryptic) and are exposed following a par-
tial denaturation of the molecule. There are many different cellular integrins; these consist of two subunits (alpha and
beta). As there are various alpha and beta subunits, the combination of these two subunits leads to the various types of
integrins (integrins are specific for cell or tissue types). Thus, some cellular integrins will be recognized by pro-
teins/glycoproteins via the presence of the RGD motif in these molecules, while other integrins will be recognized inde-
pendently of the RGD motif, i.e., by molecules that do not possess an RGD motif.
The Spike protein of SARS-CoV-2 (corresponding to a necklace of 1273 beads) has this RGD motif (motif of three
beads at positions 403 to 405 in the RBD or "Receptor Binding Domain" of the Spike protein) of attachment to integ-
rins, unlike the Spike proteins of other coronaviruses, such as SARS-CoV (2002 epidemic) or MERS-CoV (2012 epi-
demic) [10]. This suggests that the Spike protein of SARS-CoV-2 (or the vaccine Spike protein, which is modified on
two other beads at positions 986 and 987) can bind to certain cell integrins via its RGD motif. This has been confirmed
by experimental laboratory work, which has shown the binding capacity of the Spike protein to alpha-V beta-3 integrins
(present on blood platelets, macrophages, dendritic cells, activated endothelial cells, certain cells tumors, and newly
formed blood vessels) and alpha-5 beta-1 (present on fibroblasts, endothelial cells, blood cells, and others) [11]. Another
work (more worrying) by Buckley and collaborators showed that various molecules possessing the RGD motif could
induce the death programmed cell via an apoptosis mechanism by activating caspase-3, initiating the cell death mecha-
nism (caspases are proteases involved mainly in inflammatory phenomena, apoptosis, and necrosis) [12]. These data
suggest that the Spike protein, viral or vaccine, could (in parallel with the dysfunction of the renin-angiotensin system
and the overactivation of the "deleterious" AT1R receptor responsible for COVID-19 diseases [13-17]) induce a phe-
nomenon of apoptosis of certain cells via binding of the Spike protein to membrane integrins activating caspase-3 and
signaling pathways for programmed cell death. Nevertheless, according to a study based on modeling/molecular dynam-
ics, the Spike protein would be unlikely to bind strongly to integrins via the RGD motif [18]. It is noteworthy that
recognition of integrins (followed by virus endocytosis) by viral proteins possessing the RGD motif has already been
observed for the human immunodeficiency virus (HIV), the foot-and-mouth disease virus, and another adenovirus [19].
In the case of natural infection with SARS-CoV-2 or "vaccine(s)" injection(s), the potential over-stimulation of the
renin-angiotensin system (RAS) leads to the overactivation of the "deleterious" AT1R receptor (via an excess of angio-
tensin-2) [17], and to an increase in the production of collagen (which is deficient in EDS) by fibroblasts that are dermal
cells supporting connective tissue and ensuring the renewal of interstitial collagen (these cells secrete the extracellular
matrix). A major function of fibroblasts is thus to regulate the composition of the extracellular matrix with which they
interact via their membrane integrins. Thus, fibroblasts manufacture and secrete collagen alongside many other compo-
nents of the extracellular matrix, including collagenases and other enzymes, to degrade, renew and reorganize the extra-
cellular matrix. A single fibroblast can secrete various types of collagen (and other components of the extracellular ma-
trix).
CONCLUSION
Regarding SARS-CoV-2 infection and vaccine injection(s) in people with EDS, we can conclude that although
EDS is a rare genetic pathology, with an overall incidence of approximately 1 in 5000 people (highly variable inci-
dence depending on the type of EDS), we have observed that a very high number of people suffering from the most
severe cases of long COVID (post-infection or post-vaccination sequelae) presented with EDS. As mentioned earlier,
EDS is systemic and directly linked to abnormalities in the connective tissue of genetic origin (production of colla-
gen). It seems to us quite possible that the deficiency in proteins of the extracellular matrix, which target membrane
integrins, confers an exacerbated "sensitivity" to the viral or vaccine Spike protein also capable of targeting integrins,
potentially leading to cell death, via caspase-3 or other activation. Notably, the Spike protein binds to alpha-5 beta-1
and alpha-V beta-3 integrins, which are integrins also targeted by collagen (partially denatured, exposing its cryp-
tic/hidden RGD motifs), being deficient in people with EDS. Thus, it seems to us that any anti-Covid-19 vaccination
booster for these high-risk people is not desirable, the benefit/risk balance being extremely unfavorable. In the case of
SARS-CoV-2 infection, early outpatient treatment (e.g., high vitamin D supplementation) of these people seems ap-
propriate [20-22].
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.
Infectious Disorders - Drug Targets, 2023, Vol. 23, No. 3 e040123212375 Fajloun et al.
28
ACKNOWLEDGEMENTS
The authors wish to thank Mrs. Christina Sahyoun for her help in the editing of this editorial.
REFERENCES
[1] Zhao DY, Rock MB, Sandhu FA. Craniocervical stabilization after failed chiari decompression: A case series of a population with high prevalence of
ehlers-danlos syndrome. World Neurosurg 2022; 161: e546-52.
http://dx.doi.org/10.1016/j.wneu.2022.02.068 PMID: 35192974
[2] Dadras O, Afsahi AM, Pashaei Z, et al. The relationship between COVID-19 viral load and disease severity: A systematic review. Immun Inflamm Dis
2022; 10(3): e580.
http://dx.doi.org/10.1002/iid3.580 PMID: 34904379
[3] SeyedAlinaghi S, Karimi A, Mojdeganlou H, et al. Impact of COVID-19 pandemic on routine vaccination coverage of children and adolescents: A
systematic review. Health Sci Rep 2022; 5(2): e00516.
http://dx.doi.org/10.1002/hsr2.516 PMID: 35224217
[4] Fajloun Z, Kovacic H, Annweiler C, Wu Y, Cao Z, Sabatier JM. SARS-CoV-2-induced neurological disorders in symptomatic COVID-19 and long
COVID patients: Key role of brain renin-angiotensin system. Infect Disord Drug Targets 2022; 22(5): e060422203203.
http://dx.doi.org/10.2174/1871526522666220406124618 PMID: 35388764
[5] Khazaal S, Harb J, Rima M, et al. The pathophysiology of long COVID throughout the renin-angiotensin system. Molecules 2022; 27(9): 2903.
http://dx.doi.org/10.3390/molecules27092903 PMID: 35566253
[6] Mao G, Kopparapu S, Jin Y, et al. Craniocervical instability in patients with Ehlers-Danlos syndrome: Controversies in diagnosis and management.
Spine J 2022; 22(12): 1944-52.
http://dx.doi.org/10.1016/j.spinee.2022.08.008 PMID: 36028216
[7] Kuivaniemi H, Tromp G. Type III collagen (COL3A1): Gene and protein structure, tissue distribution, and associated diseases. Gene 2019; 707: 151-71.
http://dx.doi.org/10.1016/j.gene.2019.05.003 PMID: 31075413
[8] Chohan K, Mittal N, McGillis L, et al. A review of respiratory manifestations and their management in Ehlers-Danlos syndromes and hypermobility
spectrum disorders. Chron Respir Dis 2021; 18: 14799731211025313.
http://dx.doi.org/10.1177/14799731211025313 PMID: 34291699
[9] Hynes RO. Integrins: Versatility, modulation, and signaling in cell adhesion. Cell 1992; 69(1): 11-25.
http://dx.doi.org/10.1016/0092-8674(92)90115-S PMID: 1555235
[10] Bugatti A, Filippini F, Bardelli M, et al. SARS-CoV-2 infects human ACE2-negative endothelial cells through an αvβ3 integrin-mediated endocytosis
even in the presence of vaccine-elicited neutralizing antibodies. Viruses 2022; 14(4): 705.
http://dx.doi.org/10.3390/v14040705 PMID: 35458435
[11] Norris EG, Pan XS, Hocking DC. Receptor binding domain of SARS-CoV-2 is a functional αv-integrin agonist. bioRxiv 2022; 2022.04.11.487882.
http://dx.doi.org/10.1101/2022.04.11.487882
[12] Buckley CD, Pilling D, Henriquez NV, et al. RGD peptides induce apoptosis by direct caspase-3 activation. Nature 1999; 397(6719): 534-9.
http://dx.doi.org/10.1038/17409 PMID: 10028971
[13] Annweiler C, Cao Z, Papon N, Kovacic H, Sabatier JM. Counter-regulatory renin-angiotensin system: An important line of research to understand and
limit the severity of COVID-19. Infect Disord Drug Targets 2022; 22(2): e100921196331.
http://dx.doi.org/10.2174/1871526521666210910063227 PMID: 34515015
[14] Harb J, Debs N, Rima M, et al. SARS-CoV-2, COVID-19, and reproduction: effects on fertility, pregnancy, and neonatal life. Biomedicines 2022;
10(8): 1775.
http://dx.doi.org/10.3390/biomedicines10081775 PMID: 35892675
[15] Mehraeen E, Najafi Z, Hayati B, et al. Current treatments and therapeutic options for COVID-19 patients: a systematic review. Infect Disord Drug Tar-
gets 2022; 22(1): 62-73.
http://dx.doi.org/10.2174/1871526521666210726150435 PMID: 34313204
[16] El-Arif G, Farhat A, Khazaal S, et al. The renin-angiotensin system: a key role in SARS-CoV-2-induced COVID-19. Molecules 2021; 26(22): 6945.
http://dx.doi.org/10.3390/molecules26226945 PMID: 34834033
[17] El-Arif G, Khazaal S, Farhat A, et al. Angiotensin II Type I receptor (AT1R): The gate towards COVID-19-associated diseases. Molecules 2022; 27(7):
2048.
http://dx.doi.org/10.3390/molecules27072048 PMID: 35408447
[18] Othman H, Messaoud HB, Khamessi O, et al. SARS-CoV-2 spike protein unlikely to bind to integrins via the Arg-Gly-Asp (RGD) motif of the receptor
binding domain: evidence from structural analysis and microscale accelerated molecular dynamics. Front Mol Biosci 2022; 9: 834857.
http://dx.doi.org/10.3389/fmolb.2022.834857 PMID: 35237662
[19] Beaudoin CA, Hamaia SW, Huang CLH, Blundell TL, Jackson AP. Can the SARS-CoV-2 spike protein bind integrins independent of the RGD se-
quence? Front Cell Infect Microbiol 2021; 11: 765300.
http://dx.doi.org/10.3389/fcimb.2021.765300 PMID: 34869067
[20] Cao Z, Wu Y, Faucon E, Sabatier JM. SARS-CoV-2 & COVID-19: Key-roles of the renin-angiotensin system/vitamin D impacting drug and vaccine
developments. Infect Disord Drug Targets 2020; 20(3): 348-9.
http://dx.doi.org/10.2174/22123989MTA2nMzg9x PMID: 32370727
[21] Annweiler C, Cao Z, Sabatier JM. Point of view: Should COVID-19 patients be supplemented with vitamin D? Maturitas 2020; 140: 24-6.
http://dx.doi.org/10.1016/j.maturitas.2020.06.003 PMID: 32972631
[22] Annweiler C, Hanotte B, Grandin de l’Eprevier C, Sabatier JM, Lafaie L, Célarier T. Vitamin D and survival in COVID-19 patients: A quasi-
experimental study. J Steroid Biochem Mol Biol 2020; 204: 105771.
http://dx.doi.org/10.1016/j.jsbmb.2020.105771 PMID: 33065275
... Ang II is cleaved by ACE2 to produce Ang-(1-7), which interacts with the MAS1 (MAS1 Proto-Oncogene, G Protein-Coupled Receptor) [19,20] Ang-(1-9) and Ang- (1-7), respectively, which regulate the RAS favorably for hepatic and overall physiological function [12][13][14][15][16][17][18][19][20][21][22][23][24]. Recent studies have highlighted the substantial involvement of the RAS in hepatic fibrosis and activation of hepatic stellate cells (HSCs) during inflammation. ...
... Imbalances, as seen in SARS-CoV-2 infection or vaccination with mRNA encoding the spike protein, can disrupt the RAS, leading to cholestasis. The spike protein interacts with ACE2 by inhibiting its enzymatic action, resulting in RAS imbalance associated with an overabundance of Ang II deregulating ERK1/2-dependent signaling and thus affecting cholangiocyte proliferation, as well as deleterious overactivation of the Ang II/AT1R axis [15][16][17][18][19][20][21][22][23][24]. Infections or vaccinations in individuals with compromised hepatobiliary function may induce cholestasis due to cholangiocyte inflammation, particularly with the spike protein inhibiting ACE2, leading to AT1R overactivation, affecting bile proliferation, and hepatic fibrosis. ...
... Moreover, an imbalance in the RAS could be highly deleterious to the human body, as is the case with infection by the SARS-CoV-2 virus, which interacts with ACE2 (the SARS-CoV-2 receptor and a major RAS enzyme), leading to an imbalance in the RAS associated with overactivation of the AT1R receptor (Fig. 1). The symptoms of COVID-19 will ultimately be linked to RAS dysfunction, as discussed in our previously published work [9][10][11][12][13][14][15][16][17][18][19]. ...
... The Ang II/AT1R axis is the main pathway that can be affected during RAS dysregulation. We have previously reported that the deleterious episodes generated following SARS-CoV-2 infection, are the result of overactivation of the Ang II/AT1R axis [11][12][13][14][15][16][17][18][19]. Numerous deleterious effects can be produced by Ang II/AT1R signaling, such as vasoconstriction, fibrosis, inflammation, cell growth, migration, organ hypertrophy, thrombosis, production of reactive oxygen species (ROS), etc. [24,25]. ...
... the COVID-19 pathologies (the RAS controls renal, pulmonary, cardiovascular, and other autonomic functions, as well as the innate immunity and the intestinal, vaginal, oral and cutaneous microbiota). The overactivated AT1R receptor is pro-thrombotic, pro-inflammatory (with the recruitment of thrombocytes/blood platelets), pro-hypertensive, pro-oxidant, pro-hypoxemic, pro-hypoxic, pro-angiogenic, pro-fibrosing, pro-hypertrophying, and depletes nitric oxide NO (the latter is involved in inflammatory, immune, and memory phenomena) [9][10][11][12][13][14]. Thus, COVID-19 vaccination or booster shots (as well as COVID-19) may favor the occurrence of thromboembolic events when taking a contraceptive pill, such as the estrogen-progestin pill. ...
... In the end, it is important to be able to identify as early as possible the various symptoms of thromboembolism in vaccinated and/or infected persons in order to prevent severe, or even fatal, forms of anti-COVID-19 vaccination and COVID-19. The dysfunctional RAS, through its overactivated AT1R receptor, contributes to this thromboembolism in parallel with the use of the estrogen-progestin pill in adolescents and women of childbearing age [14,[17][18][19]. ...
... However, it is worth noting that vaccines can also cause thyroiditis and delayed-onset thyroid disorders [28,29]. Fajloun et al. suggest that vaccines may induce RAS dysfunction, leading to phenomena such as "antibody-dependent enhancement" (ADE) and "enhanced respiratory disease" (ERD), which increase the risk of reinfection [30,31]. Although the relationship between these phenomena and COVID-19 vaccines remains controversial, the antibody protection mechanism against any virus has the potential to amplify infection or trigger harmful immunopathology. ...
Article
Full-text available
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly, leading to an Omicron outbreak in Shanghai in mid-December after adjustments to the Coronavirus Disease 2019 (COVID-19) control strategy. To investigate the impact of COVID-19 infection among hypothyroid patients, we gathered data on the hypothyroid outpatients with COVID-19 infection during this time at the Thyroid Disease Center (TDC) of Shanghai Central Hospital. Patients were divided into two groups based on whether their hypothyroidism was caused by Hashimoto’s Thyroiditis (HT): the HT and the non-HT group. We assessed the differences between pre-infection and clinical follow-up at one month (day (D) 30) and three months (D90) after COVID-19 infection. In HT group, thyroid-stimulating hormone (TSH) levels decreased significantly compared to pre-infection levels (p = 0.013), while free triiodothyronine (FT3) levels increased at D90 compared to both D30 post-infection and pre-infection levels (p < 0.001 and p = 0.005). Hemoglobin levels also increased after COVID-19 infection (p = 0.033). For non-HT patients, FT3 levels increased at D30 compared to pre-infection levels (p = 0.017). Moreover, inactivated SARS-CoV-2 vaccination can preserve thyroid function stability in patients with hypothyroidism.
... After the COVID-19 pandemic and the introduction of vaccination based on a slightly modified SARS-CoV-2 spike protein, several comorbidities and illnesses have emerged [9,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. One of these diseases is epilepsy, where the dysfunctional RAS plays a crucial role in the propagation of the disorder. ...
Article
Full-text available
Several comorbidities and illnesses have emerged after the COVID-19 pandemic and the introduction of vaccination based on a slightly modified SARS-CoV-2 spike protein. One of these diseases is epilepsy, where the dysfunctional RAS plays a crucial role in the propagation of the disorder. SARS-CoV-2 infects host cells by utilizing the angiotensin-converting enzyme Type 2 (ACE2) receptor, which allows the virus to infect various cell types, including those in the lungs, nasopharynx, kidneys, lymph nodes, small intestine, stomach, spleen, and brain, leading to widespread organ damage. Once SARS-CoV-2 binds to the ACE2 receptor, it can lead to the overactivation of the ACE/Ang II/AT1R axis. Consequently, higher levels of Ang II activate several deleterious pathways that promote inflammation, contributing to inflammatory responses in the body and exacerbating conditions such as seizures. Additionally, the excitatory effect of AT1R by Ang II excess due to ACE2 inhibition by SARS-CoV-2 or by the vaccine Spike protein may play a further role in the mechanism contributing to epilepsy.
... There has been an increase in MAS cases attributed to the SARS-CoV-2 virus and anti-SARS-CoV-2 vaccination, with several reported instances [13,18,19]. Indeed, the SARS-CoV-2 spike protein, whether from viruses or vaccine spike protein, can induce various issues and illnesses in humans, including MAS [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. Following SARS-CoV-2 interaction with its angiotensin-converting enzyme 2 (ACE2) receptor, dysregulation of the renin-angiotensin system (RAS) occurs, resulting in elevated levels of Angiotensin II (Ang II). ...
... The viral or vaccine Spike protein can induce various major impairments and dysfunctions within the human body [8][9][10][11][12][13][14][15][16][17][18][19][20], among which is MCAS. Thus, the latter can be triggered by natural infection with SARS-CoV-2 or be directly induced by *Address correspondence to this author at the Aix-Marseille Univ, CNRS, INP, Inst Neurophysiopathol, 13385 Marseille, France; Email: sabatier.jm1@gmail.com ...
... For some people suffering from autoimmune diseases, a worsening of the disease may be observed. Furthermore, regardless of the antigen, if too many "vaccine" booster shots are given (i.e., saturating/overloading the immune system), innate immunity will inevitably be dysregulated, leading to the development of autoimmune diseases [10,[14][15][16][17]. These can affect various organs, including the thyroid. ...
... In neurological disorders, intestinal dysbiosis is observed among patients suffering from depression or anxiety, Alzheimer's or Parkinson's disease, schizophrenia, and other autistic or bipolar disorders. All of these pathologies are associated with RAS dysfunction (and overactivation of the AT1R receptor) [6,15]. ...
Article
Full-text available
Since its discovery in Wuhan, China, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread over the world, having a huge impact on people’s lives and health. The respiratory system is often targeted in people with the coronavirus disease 2019 (COVID-19). The virus can also infect many organs and tissues in the body, including the reproductive system. The consequences of the SARS-CoV-2 infection on fertility and pregnancy in hosts are poorly documented. Available data on other coronaviruses, such as severe acute respiratory syndrome (SARS-CoV) and Middle Eastern Respiratory Syndrome (MERS-CoV) coronaviruses, identified pregnant women as a vulnerable group with increased pregnancy-related complications. COVID-19 was also shown to impact pregnancy, which can be seen in either the mother or the fetus. Pregnant women more likely require COVID-19 intensive care treatment than non-pregnant women, and they are susceptible to giving birth prematurely and having their newborns admitted to the neonatal intensive care unit. Angiotensin converting enzyme 2 (ACE2), a key player of the ubiquitous renin-angiotensin system (RAS), is the principal host cellular receptor for SARS-CoV-2 spike protein. ACE2 is involved in the regulation of both male and female reproductive systems, suggesting that SARS-CoV-2 infection and associated RAS dysfunction could affect reproduction. Herein, we review the current knowledge about COVID-19 consequences on male and female fertility, pregnant women, and their fetuses. Furthermore, we describe the effects of COVID-19 vaccination on reproduction.
Article
Full-text available
COVID-19 has expanded across the world since its discovery in Wuhan (China) and has had a significant impact on people’s lives and health. Long COVID is a term coined by the World Health Organization (WHO) to describe a variety of persistent symptoms after acute SARS-CoV-2 infection. Long COVID has been demonstrated to affect various SARS-CoV-2-infected persons, independently of the acute disease severity. The symptoms of long COVID, like acute COVID-19, consist in the set of damage to various organs and systems such as the respiratory, cardiovascular, neurological, endocrine, urinary, and immune systems. Fatigue, dyspnea, cardiac abnormalities, cognitive and attention impairments, sleep disturbances, post-traumatic stress disorder, muscle pain, concentration problems, and headache were all reported as symptoms of long COVID. At the molecular level, the renin-angiotensin system (RAS) is heavily involved in the pathogenesis of this illness, much as it is in the acute phase of the viral infection. In this review, we summarize the impact of long COVID on several organs and tissues, with a special focus on the significance of the RAS in the disease pathogenesis. Long COVID risk factors and potential therapy approaches are also explored.
Preprint
Full-text available
Among the novel mutations distinguishing SARS-CoV-2 from similar respiratory coronaviruses is a K403R substitution in the receptor-binding domain (RBD) of the viral spike (S) protein within its S1 region. This amino acid substitution occurs near the angiotensin-converting enzyme 2 (ACE2)-binding interface and gives rise to a canonical RGD adhesion motif that is often found in native extracellular matrix proteins, including fibronectin. In the present study, the ability of recombinant S1-RBD to bind to cell surface integrins and trigger downstream signaling pathways was assessed and compared to RGD-containing, integrin-binding fragments of fibronectin. S1-RBD supported adhesion of both fibronectin-null mouse embryonic fibroblasts as well as primary human small airway epithelial cells. Cell adhesion to S1-RBD was cation- and RGD-dependent, and was inhibited by blocking antibodies against αv and β3, but not α5 or β1, integrins. Similarly, direct binding of S1-RBD to recombinant human αvβ3 and αvβ6 integrins, but not α5β1 integrins, was observed by surface plasmon resonance. Adhesion to S1-RBD initiated cell spreading, focal adhesion formation, and actin stress fiber organization to a similar extent as fibronectin. Moreover, S1-RBD stimulated tyrosine phosphorylation of the adhesion mediators FAK, Src, and paxillin, Akt activation, and supported cell proliferation. Together, these data demonstrate that the RGD sequence within S1-RBD can function as an αv-selective integrin agonist. This study provides evidence that cell surface αv-containing integrins can respond functionally to spike protein and raise the possibility that S1-mediated dysregulation of ECM dynamics may contribute to the pathogenesis and/or post-acute sequelae of SARS-CoV-2 infection.
Article
Full-text available
Integrins represent a gateway of entry for many viruses and the Arg-Gly-Asp (RGD) motif is the smallest sequence necessary for proteins to bind integrins. All Severe Acute Respiratory Syndrome Virus type 2 (SARS-CoV-2) lineages own an RGD motif (aa 403–405) in their receptor binding domain (RBD). We recently showed that SARS-CoV-2 gains access into primary human lung microvascular endothelial cells (HL-mECs) lacking Angiotensin-converting enzyme 2 (ACE2) expression through this conserved RGD motif. Following its entry, SARS-CoV-2 remodels cell phenotype and promotes angiogenesis in the absence of productive viral replication. Here, we highlight the αvβ3 integrin as the main molecule responsible for SARS-CoV-2 infection of HL-mECs via a clathrin-dependent endocytosis. Indeed, pretreatment of virus with αvβ3 integrin or pretreatment of cells with a monoclonal antibody against αvβ3 integrin was found to inhibit SARS-CoV-2 entry into HL-mECs. Surprisingly, the anti-Spike antibodies evoked by vaccination were neither able to impair Spike/integrin interaction nor to prevent SARS-CoV-2 entry into HL-mECs. Our data highlight the RGD motif in the Spike protein as a functional constraint aimed to maintain the interaction of the viral envelope with integrins. At the same time, our evidences call for the need of intervention strategies aimed to neutralize the SARS-CoV-2 integrin-mediated infection of ACE2-negative cells in the vaccine era.
Article
Full-text available
The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2), causes its down-regulation, which subsequently leads to the dysregulation of the renin-angiotensin system (RAS) in favor of the ACE-angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis. AT1R has a major role in RAS by being involved in several physiological events including blood pressure control and electrolyte balance. Following SARS-CoV-2 infection, pathogenic episodes generated by the vasoconstriction, proinflammatory, profibrotic, and prooxidative consequences of the Ang II-AT1R axis activation are accompanied by a hyperinflammatory state (cytokine storm) and an acute respiratory distress syndrome (ARDS). AT1R, a member of the G protein-coupled receptor (GPCR) family, modulates Ang II deleterious effects through the activation of multiple downstream signaling pathways, among which are MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases (PDGF, EGFR, insulin receptor), and nonreceptor tyrosine kinases (Src, JAK/STAT, focal adhesion kinase (FAK)), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. COVID-19 is well known for generating respiratory symptoms, but because ACE2 is expressed in various body tissues, several extrapulmonary pathologies are also manifested, including neurologic disorders, vasculature and myocardial complications, kidney injury, gastrointestinal symptoms, hepatic injury, hyperglycemia, and dermatologic complications. Therefore, the development of drugs based on RAS blockers, such as angiotensin II receptor blockers (ARBs), that inhibit the damaging axis of the RAS cascade may become one of the most promising approaches for the treatment of COVID-19 in the near future. We herein review the general features of AT1R, with a special focus on the receptor-mediated activation of the different downstream signaling pathways leading to specific cellular responses. In addition, we provide the latest insights into the roles of AT1R in COVID-19 outcomes in different systems of the human body, as well as the role of ARBs as tentative pharmacological agents to treat COVID-19.
Article
Full-text available
The Receptor Binding Domain (RBD) of SARS-CoV-2 virus harbors a sequence of Arg-Gly-Asp tripeptide named RGD motif, which has also been identified in extracellular matrix proteins that bind integrins as well as other disintegrins and viruses. Accordingly, integrins have been proposed as host receptors for SARS-CoV-2. However, given that the microenvironment of the RGD motif imposes a structural hindrance to the protein-protein association, the validity of this hypothesis is still uncertain. Here, we used normal mode analysis, accelerated molecular dynamics microscale simulation, and protein-protein docking to investigate the putative role of RGD motif of SARS-CoV-2 RBD for interacting with integrins. We found, that neither RGD motif nor its microenvironment showed any significant conformational shift in the RBD structure. Highly populated clusters of RBD showed no capability to interact with the RGD binding site in integrins. The free energy landscape revealed that the RGD conformation within RBD could not acquire an optimal geometry to allow the interaction with integrins. In light of these results, and in the event where integrins are confirmed to be host receptors for SARS-CoV-2, we suggest a possible involvement of other residues to stabilize the interaction.
Article
Ehlers-Danlos syndrome (EDS) is a rare hereditary condition that can result in ligamentous laxity and hypermobility of the cervical spine. A subset of patients can develop clinical instability of the craniocervical junction associated with pain and neurological dysfunction, potentially warranting treatment with occipitocervical fixation (OCF). Surgical decision-making in patients with EDS can be complicated by difficulty distinguishing from hypermobility inherent in the disease and true pathological instability necessitating intervention. Here we comprehensively review the available medical literature to critically appraise the evidence behind various proposed definitions of instability in the EDS population, and summarize the available outcomes data after OCF. Several radiographic parameters have been used, including the clivo-axial angle, basion-axial interval, and pB-C2 measurement. Despite increasing recognition of EDS by spine surgeons, there remains a paucity of data supporting proposed radiographic parameters for spinal instability among EDS patients. Furthermore, there is a lack of high-quality evidence concerning the efficacy of surgical treatments for chronic debilitating pain prevalent in this population. More standardized clinical measures and rigorous study methodologies are needed to elucidate the role of surgical intervention in this complex patient population.
Article
Background In the treatment of Chiari malformation Type I (CM-I), posterior fossa decompression is achieved via suboccipital craniectomy (SOC); however, some patients continue to experience symptoms after treatment which may be due to craniocervical instability (CCI). The purposes of this study were to analyze data from patients who required an occipitocervical fusion (OCF) for the management of CCI after having previously undergone SOC for CM-I to determine if OCF is a safe and effective option and to determine any identifiable risk factors for CCI in these patients. Methods A retrospective review was done on all patients who underwent an occipitocervical fusion (OCF) performed by the senior author between November 2013 and June 2020 after having previously undergone SOC for CM-I. Demographic, radiographic, perioperative, and outcome data were collected and clivoaxial angles (CXA) were measured pre- and post-operatively. Results Fifteen patients were identified who developed symptomatic CCI after previously undergoing a suboccipital craniectomy for the treatment of CM-I. All 15 patients were treated by OCF with good outcome. Of these, 12 patients had a known diagnosis of Ehlers-Danlos Syndrome (EDS). Overall, the CXAs of these patients were found to be corrected to a more anatomical alignment. Conclusions Symptomatic CCI should be recognized as a delayed postoperative complication in the surgical treatment of CM-I, with an underlying connective tissue hypermobility disorder such as EDS serving as a potential risk factor its development. CCI can be managed with OCF as a safe and effective treatment option for this patient population.