Covid-19 – Sialic Acid: A Vital Component in Cell Biology and Host-Pathogen Interactions

Sialic acid (SiA), a term encompassing a family of nine-carbon acids, is crucial in cellular biology, particularly for eukaryotic cells. These acids are components of glyco-conjugated molecules, notably glycans, on most eukaryotic cell membranes [1]. The process of sialylation, which involves adding sialic acid units to the oligosaccharide chains of glycans, is critical for vertebrate cell surfaces and secreted glycoconjugates, collectively known as the glycocalyx [2,3].

SiAs play several pivotal roles, including maintaining cell surface hydration through negatively charged water molecules, protecting glycoproteins from enzymatic degradation, facilitating intercellular adhesion, and participating in cell signaling and immunological recognition [1–4]. In addition, sialic acid is a primary component of the mucous lining, protecting various organs and bodily fluids, a feature that led to the term “sialic” [3,5].

SiAs are consistently found at the terminal ends of cell membrane polysaccharide structures in various cells, including vascular and ductal endothelial cells and specialized structures like the myelin sheath in nerve cells and gangliosides in neuronal synaptic structures [6–9].

These sialic acid-containing glycans, or sialoglycans, are recognized as specific self-associated molecular patterns (SAMPs) on healthy cells’ glycocalyx [10]. They interact with Sialic acid-binding immunoglobulin-type lectins (Siglecs), found on the surface of various immune cells, thereby playing a role in distinguishing self from non-self elements in the immune system [11]. This recognition process involves at least 16 different Siglecs and is crucial in regulating immune responses [12-15].

Alterations in glycan sialylation can have significant effects, such as modulating inflammatory responses, affecting apoptosis, aiding viral immune escape, and promoting cancer cell metastasis [3]. For example, sialylation of antibody Fc regions plays a role in maintaining immune system homeostasis by reducing inflammatory reactions [13,16]. The loss of terminal sialic acid, such as in platelets, signals their clearance from circulation [17]. Additionally, removing terminal SiA through sialidases or oxidative damage can initiate innate immune responses, especially in the nervous system [9].

Pathogens, including various bacteria and viruses, have evolved mechanisms to recognize and exploit cell surface glycans, using SiA to evade host immune defenses. This includes enveloped viruses utilizing SiA-containing receptors for cell entry and exit, a process involving neuraminidases [18]. Conversely, as a defense mechanism, sialylated O-linked glycans on mucins provide a protective barrier against pathogens [3].

Xenosialylation

Humans, along with some other mammals, lack the synthesis of N-glycolylneuraminic acid (Neu5Gc) due to a mutation in the Cytidine Monophospho-N-Acetylneuraminic Acid Hydroxylase (CMAH) gene [20,21]. Neu5Gc can be assimilated through diet or pharmaceuticals and is indistinguishably expressed on cell membrane glycans, leading to xenosialylation [23–27]. This incorporation of Neu5Gc in humans triggers various immune responses, including inflammation (xenosialitis) and the production of anti-Neu5Gc antibodies [30–32]. High levels of xenosialylation are linked to cancer, atherosclerosis, and autoimmune diseases [31,32].

The dietary intake of Neu5Gc affects gut microbiota composition and immune responses. Gut bacteria with sialidases can release Neu5Gc, contributing to gut inflammation and various diseases [4,5,36,38,39]. Pathogenic bacteria can incorporate Neu5Gc into their surface structures, enhancing their virulence and triggering stronger host immune reactions [40].

Autoimmune Disorders and COVID-19

Recent pandemics have shed light on the interplay between infectious diseases and autoimmune disorders. For instance, severe COVID-19 complications and post-vaccination side effects resemble autoimmune diseases [46]. This is due to the immune system’s response to infections and vaccinations, which can trigger or exacerbate autoimmune conditions [49–61]. Studies have linked COVID-19 with various autoimmune diseases and shown that existing autoimmune conditions can worsen the severity of COVID-19 complications [62–73].

Adverse Reactions to SARS-CoV2 Vaccination

Adverse reactions to SARS-CoV2 vaccinations are generally mild, but severe reactions can occur, particularly in individuals with pre-existing autoimmune conditions. These reactions can include inflammatory and autoimmune syndromes, sometimes accompanied by the reactivation of latent viruses [92–101]. A particular concern is the occurrence of Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT), a rare but severe reaction following adenoviral vector-based vaccines, characterized by thrombocytopenia and aggressive thrombosis [112–117].

This condition is thought to result from a two-step immune reaction, beginning with the interaction between Platelet Factor 4 (PF4) and vaccine components to generate neo-antigens, followed by anti-PF4 antibodies inducing platelet and granulocyte activation [109]. Despite its severity, the incidence of VITT is significantly lower than the risk of thrombotic complications from COVID-19 infection, underscoring the overall benefit of vaccination [100].

Gender and Age Differences in Immune Responses

The interplay between gender, age, and immune response is complex and significant, especially in the context of COVID-19. Women, who generally have stronger innate and acquired immunological responses than men, are more susceptible to autoimmune diseases, while men are more prone to neoplasms and infectious diseases [83,84]. Age-related differences in immune response are also evident in COVID-19, with older individuals typically experiencing more severe symptoms. This disparity may be partially due to differences in sialic acid expression on cell surfaces and age-related biological changes, such as epigenetic alterations and mitochondrial dysfunction [85–89].

Multi-faceted Nature of Autoimmune Disorders

Autoimmune disorders exhibit diverse immunopathogenic mechanisms. Interestingly, a person may have more than one autoimmune disease, with varying autoantibodies targeting different organs or tissues. This phenomenon supports the association with polyclonal anti-Neu5Gc antibodies, which can be directed against multiple organs and tissues, contributing to the complexity of autoimmune diseases [48].

Discussion

The discussion section of this paper delves into the complex interplay between the immune system, xenosialylation, and the observed severe inflammatory and autoimmune reactions in the context of COVID-19 infection and vaccination. The authors propose a novel hypothesis regarding the role of Neu5Gc (Xenosialic acid-XeSiA) in initiating and perpetuating these immune responses.

• Xenosialylation and Immune Response: The authors start by explaining how humans, as negative-CMAH species, have naturally developed antibodies against Neu5Gc-MCA as an adaptation strategy against viral zoonoses. These antibodies block viral infections that typically affect positive-CMAH species, thus acting as a protective mechanism against zoonotic transmission.
• Xenosialylation and Systemic Contamination: Prolonged exposure to Neu5Gc through various sources, such as diet or iatrogenic administrations, leads to the progressive contamination of cell membranes by Xenosialylation, transforming xenosialylated epitopes into potential MCAs.
• Inflammatory State and Autoimmune Response: The authors describe how the immunoreaction against Xenosialylation triggers an inflammatory state characterized by lymphocytic infiltration, cytokine release, and tissue damage. This inflammatory state leads to the production of specific anti-Neu5Gc antibodies, which target and remove xenosialylated epitopes from host tissues, resulting in de-xenosialylation.
• Impact on Vaccine Response: The discussion extends to how this mechanism might influence the immune response to vaccines. In highly xenosialylated hosts, the immune system activated by vaccines reacts against xenosialylated cell surfaces, potentially leading to an imbalance in circulating antibodies, favoring hyperactive agalactosylated antibodies. This imbalance can explain various degrees of immunological side effects observed post-vaccination.
• Gender-Specific Implications: The authors highlight that gender differences in xenosialylation distribution may account for differential clinical outcomes. They suggest that estrogen’s protective effect may influence this distribution and explain why women are more prone to autoimmune post-infective complications and post-vaccination side effects, while men are more prone to severe COVID-19 and cardiovascular disorders.
• Coagulopathies and Thrombotic Disorders: The discussion also addresses the frequent occurrence of coagulopathies during the COVID-19 pandemic and after anti-SarsCoV2 vaccination. The xeno-contamination of the endothelial vascular system, triggered by contact with anti-MCAs of xenosialylated endothelial surfaces, is proposed as an explanation for these issues, even in patients not exposed to heparin.
• Association with Autoimmune Diseases: The authors suggest that the immunological chronic reaction to the incorporation and distribution of XeSiAs-Neu5GC self-antigens can be linked to various autoimmune diseases, including Type I and II diabetes, Rheumatoid Arthritis, Multiple Sclerosis, GBS, SLE, and others.
• Neurological Implications: The heavy xeno-contamination of the nervous system is discussed in relation to the observed polyneuropathies after viral infections or vaccinations.

Conclusions and Future Directions

The discussion concludes by summarizing the hypothesis put forward in this paper. It suggests that Neu5Gc’s incorporation as a self-antigen, acting as Mammalian-associated Carbohydrate Antigens (MCAs), triggers a chronic low-grade inflammation leading to autoimmune responses and various complications. The authors propose that clinical professionals investigate this phenomenon further to identify and prevent severe complications in patients exposed to SARS-CoV2 infection or related vaccinations.

The discussion emphasizes the need for future studies to evaluate the total anti-MCA antibody titer in serum, particularly anti-Neu5GC antibodies, as a potential parameter to explain the incidence and severity of viral infections and post-vaccination adverse effects. While this hypothesis is speculative and based on a literature analysis, it provides a novel perspective on the immunological responses to infectious agents and vaccines, urging further research in this direction.

reference link : https://www.preprints.org/manuscript/202310.0001/v2