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Xenosialylation: Role in SARS/CoV-2 Post-infectious and Post-vaccination Complications and Common Cause of Hyperimmune/Autoimmune Diseases

Submitted:

30 September 2023

Posted:

01 October 2023

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Preprints on COVID-19 and SARS-CoV-2
Abstract
The host glycosylation mechanism synthesizes the carbohydrates of glycoproteins of viral envelopes. Due to the loss of the Cytidine Monophospho-N-Acetylneuraminic Acid Hydroxylase gene by some mammalian species, including humans (negative-CMAH), Neu5Gc is no longer synthesized. Uptake of Neu5Gc by negative-CMAH species, through the intake of food products derived from positive-CMAH mammals, leads to incorporating Neu5Gc-glycans in the glycocalyx (xenosialylation). Neu5Gc, being a Mammalian-associated Carbohydrate Antigen (MCA), acts as a non-self-antigen, inducing an inflammatory reaction (Xenosialitis), and triggering the production of circulating antiNeu5Gc antibodies to attack/remove all incorporated Neu5Gc. In the state of Xenosialitis, the virus-neutralizing antibodies produced by a heavily xenosialylated patient following exposure to viral infection (including SarsCoV2) or anti SarsCoV2 vaccination cross-react against all incorporated non-self Neu5Gc-MCA glycans due to their resemblance with viral envelope antigens synthesized by the host glycosylation mechanism. In addition, the circulating anti-XeSias antibodies determine the massive removal of the circulating neutralizing FC-xeno-contaminated antibodies by the serum, living only the hyper-inflammatory agalattosylated antiviral IgG antibodies. Therefore, we hypothesize that the combination of antibody cross-reaction against non-self Neu5Gc-MCA glycans and the massive removal of the xeno-contaminated newly formed neutralizing antibodies in favor of hyper reactive antibodies, could be the cause of the massive inflammatory reaction (cytokine storm, coagulopathies, neuropathies) observed in Covid 19 patients or after anti-SarsCoV2 vaccination. Therefore, evaluating the serum anti-MCA antibodies titer, particularly anti-Neu5GC antibodies, could be a groundbreaking tool to timely identify patients at risk of developing severe complications in case of all viral infections, including SARS-CoV2 and repeated vaccinations.
Keywords: 
sialic acid
;  
sialylation
;  
xeno-sialic acid
;  
COVID-19
;  
SARS-CoV-2
Subject: 
Medicine and Pharmacology  -   Immunology and Allergy
Running Title: "Xenosialylation severe COVID-19 complications/SARS-CoV-2 vaccinations"

INTRODUCTION

Sialic acid (SiA) is a generic term to indicate a large family of nine-carbon acids that are present on the glyco-conjugated molecules (Glycans) associated with the membrane surfaces of most eukaryotic cells [1]. Sialylation is the addition of sialic acid units at the terminal ends of oligosaccharide chains of the glycans incorporated in the vertebrate cell surface and secreted glycoconjugates known as glycocalyx [2,3]. The presence of SiAs on glycans confers important physiological and immunological properties, such as a negative charge of water molecules to keep the cell surface hydrated, protection of glycoproteins from protease attack, intercellular adhesion, cell signaling, and immunological recognition [1,2,3,4]. Sialic acid (SiA) represents the main component of the mucous lining; it has the function of protecting the underlying cellular strata in organs such as the intestine, lung, uterus, oviduct, spermatic ducts, glandular tissue, and most of the body fluids, including saliva, from which the term “sialic” derives [3,5]. SiA always occupies the terminal part of all the polysaccharide structures of the cell membrane glycocalyx of vascular and ductal endothelial cells, including the more specialized structures of cell membranes such as the myelin sheath of the axons of the nerve cells of the Nervous System (NS), as well as the gangliosides lining the neuronal synaptic structures [6,7,8,9]. Sialic acid-containing glycans [sialoglycans] represent the specific self-associated molecular patterns (SAMPs) on the glycocalyx of healthy cells [10]. The sialoglycans are recognized as SAMPs by Sialic acid-binding immunoglobulins type lectins (Siglecs), the specific protein receptors exposed on the surface of several immune cells (such as monocytes, macrophages, dendritic cells, natural killer cells, B lymphocytes, neutrophils, and eosinophils), myeloid progenitors, trophoblasts and osteoclasts [11]. Siglecs, by interacting with SiA of the sialoglycan-SAMPs of the same cells, as well as adjacent ones, discriminate between the body’s own (self) and foreign antigens (not-self). This means that Siglecs (e.g., CD33), as well as Factor H and CD24, have all been identified as potential SAMP-Recognizing Receptors (SAMP-RR), having the role of repressing immune responses [12,13]. There are at least 16 Siglecs expressed by different leukocyte populations [14]; some of these interpret “non-pathogen glycans” as “self” (SAMPs) and deliver inhibitory signals to immune cells to prevent them from becoming overstimulated [15]. Several studies suggested that any changes in glycan sialylation could modulate the inflammatory responses, regulate apoptosis, allow for viral immune escape, and promote cancer cell metastasis [3]. In particular, the sialylation of the Fc region of antibodies has shown to be a homeostasis that reduces the immune system’s inflammatory reaction [13,16]. It has been proved that the sialylation of the IgG Fc-glycan of the circulating antibodies has a potent and stable anti-inflammatory activity [13], while the removal/reduction of the sialic acid induced an increase of the immune reactivity and inflammatory status [13,16]. Moreover, the rapid clearance of platelets from circulation occurs through the loss of terminal sialic acid, which represents the signal for their removal and destruction [17]. Removing terminal Sia of glycoconjugates by sialidases or oxidative damage initiates a series of cell-signaling events of innate immunity, especially in the nervous system [9].
It is not at all surprising that numerous pathogens and symbionts have evolved highly specific ways to recognize aspects of the dense and complex forest of cell surface glycans they encounter in host species. SiA viral recognition has been known to be a virulence factor for several pathogens [1]. Many bacteria and viruses, as well as Adenovirus, Reovirus, Orthomyxovirus [influenza virus], and Coronaviruses, have evolved to use SiA to evade the host’s immune system. SiA participates, directly and indirectly, in the “coating” and “budding” of many enveloped viruses. Enveloped viruses use receptors containing SiA, for example, ACE2 receptors, to enter and subsequently exit the cells, thanks to their neuraminidases [enzymes capable of binding the terminal SiA of the specific receptor [18]. These interactions often involve Glycan-Binding Proteins [GBP] and can result in symbiosis, commensalism, or disease [3]. On the other hand, as a host defense mechanism, sialylated O-linked glycans covering mucins on mucosal cell surfaces provide a large layer of sialylated residues that act as a barrier, preventing pathogens from entering the cell by offering a decoy alternative binding site [3].

XENOSIALYLATION

Most mammals express two common SiAs: N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) [19]. However, humans, ferrets (mustelids – weasel family), and few other mammals (bats, procyonids, pinnipeds) are deficient in Neu5Gc synthesis because of a specific mutation inactivating the Cytidine Monophospho-N-Acetylneuraminic Acid Hydroxylase (CMAH), gene responsible for converting CMP-Neu5Ac to CMP-Neu5Gc [20,21]. In humans, Neu5Gc (originally called non-human-SiA) [22], here named XeSiA-Neu5Gc, can be assimilated by dietary products, such as edible mammalian meat, milk, fish eggs (but not fish muscles) and edible echinoderms or can, also, be introduced by therapeutic administration of pharmaceutical preparations deriving from non-human cells cultured in vitro, as well as glycosylated biopharmaceutics such as recombinant glycoproteins [23,24]. Since human biochemical and cellular pathways cannot distinguish Neu5Gc from Neu5Ac, the assimilated XeSiAs-Neu5Gc are indifferently exposed on cell membrane glycans of the host cell surface, causing Xenosialylation [23,24,25,26,27]. It has been shown that XenoSiAs-Neu5Gc-glycoproteins ingested from food intake are incorporated into the enterocytes of the small intestinal tract and then appear in circulation at a steady-state level for several hours, followed by the metabolic incorporation into multiple glycoproteins and glycolipids of the entire body tissues as well as in vascular glycocalyx of the entire circulatory system or gangliosides of the peripheral and central nervous system in relation to the cellular SiAs turn-over [19,28]. The immune system recognizes the exposed XeSiAs-Neu5Gc, as a “not-self” (PAMPs) embedded in the context of the “self” (SAMPs), firstly by T lymphocytes TLRs (innate immune system), which trigger the release of local inflammatory cytokines against the XeSiA-Neu5Gc (inflammatory condition of Xenosialitis), and, secondly, by lymphocytes B stimulation, which starts to produce circulating anti-Neu5Gc antibodies (adaptative immune system), which permanently remove all incorporated XeSiAs-Neu5Gc (de-xenosialylation). The incorporated XeSiAs are Mammalian-associated Carbohydrate Antigens (MCAs) [30], which trigger an auto-immune reaction [30,31,32] like after exposure to mammalian serum [serum sickness] [22,32] or xenograft [29].
It has been demonstrated that a high levels of Xenosialylation of the cell surface, and relative inflammatory Xenosialitis condition, is associated with the long-term appearance of cancer, atherosclerosis, and several autoimmune diseases [31,32]. The appearance of circulating anti-Neu5Gc antibodies has been observed during the first year of life (early xenosialylation), and it is correlated with the presence of XeSiAs-Neu5Gc in the diet (mainly by mammalian xenosialylated milk and meats, particularly belonging to ruminants) of children not breastfed (bottle-feeding) or in early weaned ones [34,35]. Introducing the XeSiA-Neu5Gc into the host gut has an important impact on the intestinal microbiome composition [36,37]. It is currently known that a Neu5Gc-rich diet induces changes in the gut microbiota, which can assimilate the xeno-glycans derived from food and seems to be responsible for immunoglobulins (IgM, IgG, and IgA) variations against Neu5Gc. XeSiAs-Neu5GC bound to milk oligosaccharides and/or mucin/muscles-derived glycans of ruminants or other edible positive CMAH species are released by gut bacteria possessing sialidases (i.e., clostridia and bacteroides); free XeSiAs, not used as a carbon source by gut bacteria, are delivered and can be assimilated by intestinal cells or can be incorporated on the gut bacteria surface, determining gut hypersensitivity to bacterial metabolites and toxins, recurrent intestinal inflammation, and infant and adult autoimmune diseases [4,5,36,38,39]. Bacterial sialidases that cleave sialic acid residues from complex glycan structures are unaffected by innate immune mechanisms and can synergize with other virulence factors, such as toxins [40]. Many bacterial adhesins and major classes of toxins as bacterial surface structures, such as lipo-oligosaccharide (LOS), lipopolysaccharide (LPS), and polysaccharide capsules, contain SiA and glycans as receptors [40]. During biosynthesis, most human-adapted pathogens integrate on their bacterial surface structures, the SiA-Neu5Ac, as a prevalent form to mimic the host and subvert the human host immune system [40]. However, the bacterial sialidases can cleave all types of sialic acid residues from complex glycan structures, allowing the incorporation of the foodborn-free XeSiA-Neu5Gc by gut bacteria transforming the gut microbiome in “Xeno-enhanced Microbiome”. This mechanism exacerbates bacterial virulence factors, such as pathogen toxins [40], and enhances the host inflammatory immune reaction at the host gut level [32]. The consequences of exposure to a “Xeno-enhanced Microbiome” are chronic inflammatory response at the gut epithelial tract with gut hypersensitivity to bacterial metabolites and toxins, recurrent intestinal inflammation, predisposing to inflammatory gut permeability, thus facilitating the onset of infant and adult autoimmune diseases [4,5,36,38,39] and of diet-related colon carcinomas [32,38,41].
It has been reported that patients with cancer have circulating heterophile antibodies that agglutinate animal red cells via recognition of the mammalian cell surface XeSiA-Neu5Gc [33]. Also, it has been demonstrated that human anti-Neu5Gc antibodies interact with metabolically incorporated Neu5Gc (state of Xenosialylation) in the tissues or organs of the host to promote local chronic inflammation (inflammatory state of Xenosialitis), therefore contributing not only to diet-related carcinomas and tumor progression [41] but also to the onset of vascular inflammation (atherosclerosis, coagulopathies) and autoimmune diseases [32]. It has been documented that the circulating anti-Neu5Gc antibodies are also involved in atherosclerosis, type 2 diabetes, and “Latent Autoimmune Diabetes in Adults” (LADA) [31,42,43,44]. Furthermore, Multiple sclerosis (MS), Guillain-Barré syndrome (GBS), Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE), Autoimmune thyroid disease, Kawasaki disease (KD), post-COVID-19 Multisystem Inflammatory Syndrome in Children (MIS-C), and Adults (MIS-A), are some of the autoimmune diseases in which autoantibodies (Xeno-autoantibodies) are always detectable in the host serum [45,46,47]. Although clinically different, all autoimmune disorders share common immunopathogenic mechanisms. Moreover, interestingly, one Autoimmune Disease (AD) may coexist with others (i.e., poly-autoimmunity), which may exhibit different autoantibodies with different specificities supporting the correlation with polyclonal anti Neu5Gc antibodies directed to several organs/tissues [48].

RECURRING COMPLICATIONS RELATED TO VIRAL INFECTIONS: AUTOIMMUNE DISORDERS

This new pandemic has made it possible to collect a significant amount of data from all over the world about post-infective complications and post-vaccination side effects. The severe complications observed in some Covid-19 patients, both elderly and very young, and all the severe side effects after anti-SarsCoV2 vaccinations are very similar to the complications/side effects following many other viral infections/vaccinations. Based on epidemiological and experimental evidence, there is a growing awareness of the role of infectious diseases in the onset of autoimmune disorders [46]. Literature refers that most patients showing severe complications during or after Covid 19 diseases are affected by comorbidities, which recognize an autoimmune cause predisposing to a higher incidence of such severe complications. Generally, immunological diseases are classified into three major groups: autoinflammatory, autoimmune, and mixed pattern [49]. Many common diseases with strong inflammatory components could be classified as predominantly autoinflammatory, although most conditions also have evidence for autoimmunity in the clinical setting. This means that all immunological diseases can be conceptualized as being purely autoinflammatory or autoimmune or a combination of autoinflammatory-autoimmune mechanisms that variably interact in the phenotypic expression of disease [49]. Associations between viral infections and autoimmune diseases have been reported repeatedly in the literature [50]. Active human cytomegalovirus (HCMV) infection is often found in patients diagnosed with Immune Thrombocytopenic Purpura (ITP) [51] and in SLE [52]. Another virus with a reported association with SLE is the Epstein-Barr virus (EBV] [53,54]. High titers of anti-EBV antibodies are also present in patients affected by RA [55]. Other examples of viral infections linked to autoimmune diseases such as islet autoimmunity and type 1 diabetes include enteroviruses (e.g., coxsackievirus A4, coxsackievirus A2, and coxsackievirus A16) and measles, mumps and rubella [56,57]. Antibodies against several common human coronaviruses have been linked with autoimmunity in people with MS, SLE, Sjögren’s syndrome, and mixed connective tissue disease [58,59,60]. Considering these associations between coronaviruses and autoimmunity and the sequence similarity of SARS-CoV-2 to these viruses, the same link between SARS-CoV-2 and autoimmunity is highly plausible [61]. To our knowledge, numerous studies demonstrated that COVID-19 is associated with a different degree of risk for various autoimmune diseases [62]. Many authors recognize a correlation between the complications of COVID-19 disease and the GBS, autoimmune hemolytic anemia, thyroiditis, Immune Thrombocytopenia (ITP), and KD [63,64,65,66,67]. Moreover, another series of studies has shown that COVID-19 leads to an aggravation of auto-immune pathologies already present in the patient, such as MS, SLE, or different forms of coagulopathy [68,69,70,71,72,73]. Most Covid-19 patients who develop severe complications are systematically affected by a large variability of autoimmune/chronic inflammatory immune-related comorbidities such as antiphospholipid syndrome (APS), systemic vasculitis, systemic autoimmune diseases, GBS, Kawasaki syndrome and MIS-C [66,74,75,76,77,78,79]. Studies report the concomitant or following COVID-19 disease of autoimmune-like and hyperinflammatory vascular/neurological manifestations such as the secondary hemophagocytic lymph-histiocytosis (HLH), ITP, Autoimmune Hemolytic Anemia (AIHA), thrombotic events associated with anti-Phospholipid antibodies (aPLs) and Lupus Anticoagulant (LAC) as in the Antiphospholipid Syndrome (APS), GBS and neurologic sensory-motor demyelinating syndrome resembling GBS, Miller Fisher Syndrome, Kawasaki-like disease, arthritis, skin manifestations [39,78,80]. A recent study reported an unusually high level of antibodies to GBS glycans in 15% of Covid-19 patients and to several other glycolipids not associated with GBS, such as GD3, fucosyl-GM1, GM2, and GM3 >35-fold higher than the largest signals in the control group; when considering all the glycolipids (GBS and non-GBS), 35% of the patients had high antibodies to at least one glycolipid [81]. Interestingly, antibody signals to gangliosides did not correlate with IgG titers to the spike protein, supporting the hypothesis that the severe complications resembling autoimmune diseases in Covid-19 are not due to viral circulation or direct viral cell damage [81]. After a SARS-CoV2 infection, often regardless of its severity, many patients continue to show clinical signs of debilitation, easy fatigue, concentration difficulties, and memory problems, even for several months, experiencing the so-called “Long COVID” syndrome [82]. This syndrome, more frequent in women, may result from poly-organ damage induced either by the excessive inflammatory response activated by the virus or by an autoimmune reaction unmasked by SARS-CoV-2 [82]. Women would be more exposed to this syndrome as they have stronger innate and acquired immunological responses than males, and both genes and hormones are involved in this sexual difference [83]. These different dynamics in immune response between women and men can explain why there is a higher incidence of autoimmune diseases in women, while in men, the susceptibility to neoplasms and infectious diseases is higher [83,84]. Morniroli et al., 2020 [85] postulated that the epidemiologic characteristics of COVID-19 [greater severity in male and older individuals] might be partially explained by the sex and age-related differences of sialome among humans and that COVID-19 clinical manifestations differ according to individual differences in the sialic acid expression on cell surfaces. Similarly, Torres-Acosta and Singer, 2020 [86] speculated that SARS-CoV-2’s ability to affect T lymphocyte and myeloid cell physiology, coupled with age-related maladaptive biological phenomena (epigenetic alterations and mitochondrial dysfunction, telomere attrition, and cellular senescence, altered intercellular communication), explains the strong association between advanced age and increased risk of COVID-19-related morbidity and mortality. The authors explain the similarity of the ARDS, induced by both Sars-CoV-2 and Influenza A virus, as an “immunological reaction” to the presence of viral RNA in the host cell cytoplasm during the replication cycle. Indeed, they activate similar intracellular antiviral pathways and subsequent recruitment of similar immune cells to the respiratory epithelium [87,88,89]. This is the same mechanism observed in many autoimmune diseases, e.g., Kawasaki Syndrome [90], as well as in many other viral infections, including influenza, in which the Macrophage Activation Syndrome [MAS] - a life-threatening clinical entity - occurs [87]. However, these hypotheses do not explain why the same reactions, considered by all authors mentioned above to be related to age and aging, occur in very young patients with autoimmune syndromes such as Kawasaki Syndrome [90,91]. Furthermore, these hypotheses do not explain the constant correlation between the severe complications in some cases of Covid-19 and comorbidities such as diabetes, atherosclerosis, cardiovascular diseases, etc.

ADVERSE REACTIONS AFTER SARS-CoV2 VACCINATION

The commonly reported adverse events after SARS-CoV2 RNA vaccination are usually mild and self-limited, including pain, redness or swelling at the site of vaccine injection, headache, fever, fatigue, myalgia, muscle pain, nausea, vomiting, itching, chills, joint pain and rarely anaphylactic shock [92]. Generally, these reactions are not associated with serious illness. Most mild symptoms post-vaccination are very similar to the same non-serious symptoms of SarsCoV-2 infection but without the involvement of the respiratory tract [93]. Data monitoring conducted as part of the US vaccination program indicates that most non-serious adverse reactions occur within two days of vaccination and almost all within seven days [94,95]. Until now, only a case of reported COVID-19 vaccine-related liver injury, classified as autoimmune hepatitis, has been described [96] in a patient 26 days after the injection of the first dose of the vaccine (Oxford-AstraZeneca). The occurrence of adverse effects is reported to be lower in the Pfizer/BioNTech vaccine compared to the Moderna vaccine [93]. However, it is worth noting that more severe post-vaccination reactions to the anti SarsCoV2 vaccine are accompanied or followed by similar inflammatory/autoimmune syndromes induced by SarsCoV-2 infections in Covid-19 diseases [97,98], as well as by many other neurological and vascular disorders [99]. Sometimes, the phenomenon is accompanied by the reactivation of latent viruses, such as Epstein Barr Virus [100] or Herpes Viruses [99,101], particularly in patients with pre-existing autoimmune diseases.
Similar complications, mainly at the neurological or vascular level, have also been reported in the case of IAV or Herpes Zooster vaccination [102,103,104]. Differences between sex and age have been observed in the vaccine biology field. It is well established that, compared to males, which showed a prevalence of myocarditis and pericarditis [105], females develop higher antibody responses related to autoimmune diseases and report more adverse reactions following vaccination [106,107]. In late February 2021, atypical thrombotic events following immunization with the adenoviral vector-based vaccine were first reported, and similar events have also been observed in recipients of other adenoviral vector-based vaccines and the mRNA-based vaccines [100,108,109,110,111]. Adverse reactions [thrombus formation] have been reported after the administration of Oxford–AstraZeneca chimpanzee adenovirus vectored vaccine ChAdOx1 nCoV-19 (AZD1222) [112], which has led several European countries to discontinue the administration of this vaccine [113].
These manifestations of coagulopathies, such as atypical thrombosis and thrombocytopenia following anti-SarsCoV2 vaccine immunization, are collectively referred as Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT) or Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) or Thrombosis with Thrombocytopenia Syndrome (TTS) [114,115,116]. The clinical features of the vaccine-induced phenomenon consisted of severe thrombocytopenia, aggressive thrombosis, and Disseminated Intravascular Coagulation (DIC), which resembles the coagulopathy seen in patients with Heparin-induced thrombosis (HIT) [117]. A study suggested that VITT is generated by a 2-step mechanism [109]. First, Platelet Factor 4 [PF4] interacts with vaccine components [including adenovirus hexon protein] to generate neo-antigens [109]. Second, anti-PF4 antibodies induce platelet and granulocyte activation 5–20 days after vaccination, driving the release of Neutrophil Extracellular Traps (NETs) that induce immune-thrombotic pathways, which may lead to clinical complications [109]. Although these events bear clinical resemblance to auto-immune heparin-induced thrombocytopenia (HIT), most cases had no known exposure to heparin before the onset of illness [109,118]. Alternatively, endogenous glycosaminoglycans present in the endothelial glycocalyx, resembling exogenous heparins, may play a role in the aberrant immune response in VITT cases. Damage to the glycocalyx may release fragmented forms of glycosaminoglycans that trigger an immune response upon electrostatic interactions with PF4 [119]. Early reported mortality rates amongst patients with Vaccine-Induced Thrombotic Thrombocytopenia (VITT), especially those with cerebral venous sinus thrombosis (CVST), were high, ranging between 30% and 60% [109]. However, it is still unclear why this immune-mediated thrombosis manifests mainly in the cerebral vessels and splanchnic circulation [118]. It should be noted that the risk of VITT remains far lower than the risk of thrombotic complications stemming from COVID-19 infection, especially for severe hospitalized cases, and thus the benefit of vaccination still outweighs the risks [100].

DISCUSSION

Human natural antibodies against Neu5Gc-MCA, synthesized by negative-CMAH mammalian species, including humans, represent an adaptation strategy against viral zoonoses for blocking viral infections affecting positive-CMAH species [30]. By producing anti- Neu5Gc-MCA antibodies, negative-CMAH species, as humans, can block the potential zoonotic passage of viruses, normally confined to one or a few other positive-CMAH mammalian species [120]. The carbohydrate chains of the viral envelopes and their spikes are synthesized using the host glycosylation mechanism therefore, they are antigenically like the carbohydrate chains of a mammalian host [30]. However, a prolonged intake of Neu5Gc by humans, through administration of serum/pharmacologic derivatives [23,24] or, more frequently, through the intake of products derived from the tissues of positive CMAH mammals (meat, dairy) [28] - particularly in the presence of a microbiota poor in de-sialylating bacteria belonging to Clostridiales and Bacteroidales [36] - leads to progressive systemic contamination of the cell membranes by XeSia-Neu5Gc, also called Xenosialylation of the host, transforming all xenosialylated epitopes in a potential MCAs. The immunoreaction against the XeSiAs-Neu5GC-MCAs starts an inflammatory state characterized by lymphocytic infiltration, release of inflammatory cytokines, and tissue damage followed by production of specific anti-Neu5Gc antibodies, which attack/remove all the incorporated XeSiAs-Neu5GC-MCAs on host tissue (de-xenosialylation), including circulating antibodies contaminated at the FC region by Xeno-Neu5Gc. If xenosialic acid continues to be available from the diet or iatrogenic administrations, an uninterrupted vicious circle is established involving the persistence of related symptoms and the onset and/or exacerbation of autoimmune, neurological, or vascular disorders. It is well known that when an infectious agent infects the host (spontaneous viral infection) or is inoculated as a specific antigen for vaccination, the immune system triggers a systemic alarm to localize and identify the presence of the pathogen/antigen. We assume that, in a situation of pre-existing heavy xenosialylation and active state of Xenosialitis, with high levels of circulating anti-XeSiA-Neu5Gc-MCAs antibodies, neutralizing antiviral antibodies produced for fighting the SarsCoV2 infection, cross-react with all the xenosialylated XeSia-Neu5Gc-MCA epitopes due to their antigenic resemblance with the virus envelope antigens of those viruses that use the host glycosylation mechanism for forming their envelope, as SARS CoV-2 as well as other enveloped viruses (i.e., IAV). It is also plausible that the rapid and massive production of neutralizing viral antibodies to fight the ongoing viral infection causes the massive XeSiA contamination of the Fc-glycans of the newly formed antibodies (mainly IgG) which will be targeted by the T lymphocytes inflammatory reaction, thus altering the balance between circulating inflammatory and anti-inflammatory antibodies in favor of hyperactive ones (agalactosylated antibodies) [13], typically observed in inflammatory/autoimmune diseases [13,16,121]. Therefore, in relation to the grade of contamination of the MCA epitopes and circulating neutralizing antibodies serum level, the host’s immune reaction becomes exasperated, massive, and widespread. This justifies and explains all the various forms of cytokine storm around 15 days after Covid-19 diseases, as well as the coagulopathies, neuropathies, and all the forms of adverse immunologic reactions currently observed in the last SarsCoV2 pandemic, both in adults and children, as reported in severe inflammatory clinic entity of Covid 19 and the Long Covid syndrome [90,122], but also observed after other severe pandemics (mainly IAV pandemics) [123].
The same mechanism comes into play when the vaccine alarm is activated in a highly xenosialylated host. In fact, the immune system activated by the inoculated antigen reacts against every xenocontaminated cell surface, also altering the balance of circulating antibodies in favor of hyperactive agalactosylated antibodies, thus triggering all the different degrees of immunological side effects reported in the literature [43,44,124]. This phenomenon explains the onset or exacerbation of several types of the reported autoimmune disorders, after vaccine adverse reactions, including the anti SarsCoV2 vaccination. The same massive production of autoantibodies is reported both in the Long Covid complications and post-vaccination adverse reactions [122].
The clinical entities of dysregulated immune reactions, which are differentiated between the genders [125], are related to the different distribution of the xenosialylated epitopes. The xenosialylation involves all the ACE Receptors (which contain Sialic acid for virus entering), and sex hormones mediate their distribution in association with the protective effect of the estrogens during the fertile phase of a woman’s life [83,84,106,107]. The state of Xenosialylation and, consequently, Xenosialitis inflammatory state can, therefore, explain why the coagulopathies and clot disorders are so frequent, especially in women than in men, and why men are more prone to severe Covid-19 diseases and myocarditis and cardiovascular disorders than women who, on the other hand, are more prone to develop autoimmune post-infective complications and post-vaccination side effects.
Moreover, the high frequency of all types of coagulopathies observed both during the Covid-19 pandemic and after antiSarsCov2 vaccination can be explained by the xeno-contamination of the endothelial vascular system, in which the contact with the Anti-MCAs of the xenosialylated endothelial surface triggers the platelet activation and NETs formation, inducing the thrombotic phenomenon also in patients which never have been exposed to heparin.
In our opinion, it is highly plausible that heterogeneous autoimmune clinical entities such as Type I, II, and LADA diabetes, Rheumatoid Arthritis, Multiple Sclerosis, GBS, SLE, and many others, as all the described Thrombotic disorders, could be caused by the immunological chronic reaction to the individual incorporation and distribution of XeSiAs-Neu5GC self-antigens in the specific districts/organs [43,44]. The neurological syndrome observed both in the Long Covid complications and after the anti-SarsCoV2 vaccination can be explained by the high concentration of sialic acid (75% of Sialic acid is concentrated in the Nervous System) at the level of the structural gangliosides of the Nervous System for which the xeno-sialization of this district can trigger serious inflammatory/autoimmune consequences [9]. The heavy xeno-contamination of the nervous system and related inflammatory/autoimmune reactions can cause the polyneuropathies reported both after spontaneous viral infection or vaccinations.

CONCLUSIONS AND FUTURE DIRECTIONS

The severe complications observed in some Covid-19 patients, both elderly and very young, and after anti-SarsCoV2 vaccinations are like those observed in all other viral infections/vaccinations (typically after infection and/or vaccination against Influence Virus A - IAV, Epstein Barr Virus – EBV). This means that the mechanism of such exasperated inflammatory/autoimmune reaction is common to all viral infections and vaccinations. The collected pandemic data demonstrates/confirmed that most of these patients are affected by other comorbidities that recognize an autoimmune cause predisposing to a higher incidence of those severe complications. In this review, we illustrate a new theory to explain the relationship between the severe inflammatory reactions observed in Covid-19 patients or after the anti-SarsCoV2 vaccination and the inflammatory/hyperimmune/autoimmune diseases commonly observed.
We postulate the role of the not-self Neu5Gc (Xenosialic acid-XeSiA), incorporated on host Glycans as a self-antigen, acting as Mammalian-associated Carbohydrate Antigens [MCAs], as a common cause of all the severe inflammatory/autoimmune reactions observed both in severe cases of Covid-19 and/or anti SarsCoV2-vaccinations. The incorporation of Xenosialic acid on host organs and tissues triggers a simultaneous response of the innate immune system against all the previously incorporated xeno-antigen Neu5Gc, therefore initiating a “vicious circle” in which the presence of the xeno-antigen Neu5Gc triggers the inflammatory state of Xenosialitis with lymphocyte infiltration, cytokine activation against the exposed xeno-sialic antigens and produces anti xeno antigens antibodies which continuously attack/remove the xeno-Sias contaminated epitopes. The chronic low-grade inflammation towards the xeno-sialic acid, covering the cell surface of the organ/tissue, in which the turnover of xeno sialic acid is continuative, is the first step for determining the stochastic production of autoimmune antibodies and onset of relative organ autoimmune disease (type 1 diabetes, Hashimoto Thyroiditis, SLE, MS, RA, GBS, etc.). In case of a viral infection, such as that sustained by SARS CoV-2 or after anti-SarsCoV2-vaccination, in a heavy xenosialylated host presenting with a high grade of inflammatory state of Xenosialitis, it is highly probable and plausible that the virus-neutralizing antibodies, produced to combat the “antigenic alarm”, indiscriminately cross-react against all MCA-contaminated XeSiA-Neu5Gc epitopes exacerbating the pre-existing condition of xenosialites and related forms of autoimmune pathology. Furthermore, the massive removal of newly formed xeno-contaminated neutralizing antibodies, in favor of those hyperreactive antibodies not containing Sias, also contributes to the amplification and exacerbation of all inflammatory/autoimmune reactions.
Based on this hypothesis, further studies could aim at evaluating serum total anti-Neu5Gc antibodies level as a possible tool to identify patients at risk of severe complications, as well as the development of a Long-Covid syndrome, both when exposed to natural infection by SARS-CoV2, or when exposed to repeated administrations of vaccine.
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Author Contributions

Fiorella Carnevali and Giacomo Rossi conceived and wrote the manuscript; Sara Mangiaterra revised and integrated the manuscript and bibliography. All authors read and approved the final manuscript.

Funding

no funding was provided for this study.

Acknowledgments

Thanks to Dr. Paola Pocek for the revision of the English language.

Conflicts of Interest

The authors declare that they have no competing interests.

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