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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.
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