Absence of Neu5Gc and Presence of Anti-Neu5Gc Antibodies in Humans—An Evolutionary Perspective

Altman, Meghan O.; Gagneux, Pascal

doi:10.3389/fimmu.2019.00789

Cited by 79 publications

(76 citation statements)

References 72 publications

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“…Neu5Ac has an acetyl group on the fifth carbon atom (C5) while Neu5Gc has a glycolyl group instead. Interestingly, humans lack Neu5Gc caused by the mutation of the cytidine monophosphate N-acetylneuraminic acid hydroxylase (CMAH) gene that codes the enzyme transforming CMP-Neu5Ac to CMP-Neu5Gc [3][4][5]. However, Neu5Gc is still found in the human glycome as it can be obtained through dietary sources [6].…”

Section: Introductionmentioning

confidence: 99%

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

Zhou

Yang

Guan

2020

Cells

131

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Sialic acids, a subset of nine carbon acidic sugars, often exist as the terminal sugars of glycans on either glycoproteins or glycolipids on the cell surface. Sialic acids play important roles in many physiological and pathological processes via carbohydrate-protein interactions, including cell–cell communication, bacterial and viral infections. In particular, hypersialylation in tumors, as well as their roles in tumor growth and metastasis, have been widely described. Recent studies have indicated that the aberrant sialylation is a vital way for tumor cells to escape immune surveillance and keep malignance. In this article, we outline the present state of knowledge on the metabolic pathway of human sialic acids, the function of hypersialylation in tumors, as well as the recent labeling and analytical techniques for sialic acids. It is expected to offer a brief introduction of sialic acid metabolism and provide advanced analytical strategies in sialic acid studies.

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Section: Introductionmentioning

confidence: 99%

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

Zhou

Yang

Guan

2020

Cells

131

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“…In addition to its absence in humans, Neu5Gc was found to be absent in some mammalian groups such as New World monkeys, sperm whales, ferrets and white-tailed deer [109]. These observations may suggest that the scenario of catastrophic selection by elimination of Neu5Gc and the ensuing production of natural anti-Neu5Gc antibody, as that in hominins, also occurred in the course of evolution of several mammalian species.…”

Section: Suggested Significance Of Viral Neu5gc Interaction With Antimentioning

confidence: 87%

“…The synthesis of Neu5Gc in many mammalian and primate cells vs. the absence of this antigen and production of natural anti-Neu5Gc antibody in humans raised the possibility that multiple zoonotic viruses replicating in various mammalian reservoirs are likely to present Neu5Gc on their envelope glycans and that anti-Neu5Gc antibody may serve as an immune barrier against infections by such viruses [63,109]. Recent studies indeed demonstrated complement-dependent virolysis of vesicular stomatitis virus (VSV) presenting Neu5Gc (i.e., replicating in African Green monkey Vero cells) by natural anti-Neu5Gc antibody within human serum [63].…”

Section: Distribution Of Neu5gc and Lysis Of Viruses Presenting Itmentioning

confidence: 99%

Host Synthesized Carbohydrate Antigens on Viral Glycoproteins as “Achilles’ Heel” of Viruses Contributing to Anti-Viral Immune Protection

Galili

2020

IJMS

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The glycans on enveloped viruses are synthesized by host-cell machinery. Some of these glycans on zoonotic viruses of mammalian reservoirs are recognized by human natural antibodies that may protect against such viruses. These antibodies are produced mostly against carbohydrate antigens on gastrointestinal bacteria and fortuitously, they bind to carbohydrate antigens synthesized in other mammals, neutralize and destroy viruses presenting these antigens. Two such antibodies are: anti-Gal binding to α-gal epitopes synthesized in non-primate mammals, lemurs, and New World monkeys, and anti-N-glycolyl neuraminic acid (anti-Neu5Gc) binding to N-glycolyl-neuraminic acid (Neu5Gc) synthesized in apes, Old World monkeys, and many non-primate mammals. Anti-Gal appeared in Old World primates following accidental inactivation of the α1,3galactosyltransferase gene 20–30 million years ago. Anti-Neu5Gc appeared in hominins following the inactivation of the cytidine-monophosphate-N-acetyl-neuraminic acid hydroxylase gene, which led to the loss of Neu5Gc <6 million-years-ago. It is suggested that an epidemic of a lethal virus eliminated ancestral Old World-primates synthesizing α-gal epitopes, whereas few mutated offspring lacking α-gal epitopes and producing anti-Gal survived because anti-Gal destroyed viruses presenting α-gal epitopes, following replication in parental populations. Similarly, anti-Neu5Gc protected few mutated hominins lacking Neu5Gc in lethal virus epidemics that eliminated parental hominins synthesizing Neu5Gc. Since α-gal epitopes are presented on many zoonotic viruses it is suggested that vaccines elevating anti-Gal titers may be of protective significance in areas endemic for such zoonotic viruses. This protection would be during the non-primate mammal to human virus transmission, but not in subsequent human to human transmission where the virus presents human glycans. In addition, production of viral vaccines presenting multiple α-gal epitopes increases their immunogenicity because of effective anti-Gal-mediated targeting of vaccines to antigen presenting cells for extensive uptake of the vaccine by these cells.

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“…However, the sialic acid family includes several derivatives of the nine-carbon sugar neuraminic acid. In pigs, apes, and Old World nonhuman primates, N-glycolylneuraminic acid (Neu5Gc) is the non-Gal antigen primarily expressed but in humans it is N-acetyneuraminic acid (Neu5Ac) [10]. These innate anti-Neu5Gc antibodies inevitably provoke chronic inflammation that chiefly contribute to the side effects from the use of porcine SIS-ECM [11].…”

Section: Introductionmentioning

confidence: 99%

The Scaffold Derived from GGTA1 and CMAH Gene Knockout Pigs Generated by Gene Editing Provoked Little Inflammatory Responses in a Humanized Pig Model

Yen¹,

Tai²,

Peng³

et al. 2020

Preprint

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BackgroundThe porcine small intestinal submucosa ECM (SIS-ECM) has been used as a supportive scaffold for healing in a variety of tissues. However, the outcomes of its application are far from satisfactory. ResultsThe possibility of generating a porcine small intestinal submucosa extracellular matrix (SIS-ECM) that is fully biocompatible was investigated. Samples of SIS-ECM were prepared from either domestic wildtype (WT) or double-gene knockout (dKO) pigs without antigenic responses to α-Gal and Nglycolylneuraminic acid (Neu5Gc). The scaffolds, which were sutured into cuts made in the longissimus muscle of the dKO pigs, were expected to exhibit xeno-reactions through natural antibodies as in a human response. A process was established to manufacture ameliorating acellular porcine SIS-ECM implants with consistent quality characteristics, which were assured by analyzing the level of residual DNA, the glycosaminoglycan content, and histochemical stains. Once implanted, the acellular SIS-ECM from the WT pigs caused a significant increase in serum IL-6 levels in the dKO recipient pigs, indicating a host defense through immune reactions. The levels remained unchanged when preparations from the dKO pigs were used. The pathological score of the multinuclear giant cells of the dKO (WT) group (2.3±0.5) was significantly greater than that of the dKO (dKO) group (0.7±0.3). ConclusionThe IL-6 levels and pathological evidences suggested that dKO pigs without α-Gal or Neu5Gc antigenic causing lower inflammatory response can serve as biocompatible SIS-ECM donors or as animal models for testing anthropomorphic immune responses to biomedical devices. BackgroundThe extracellular matrix (ECM) is a noncellular structure required for the process of forming a new networks and tissues and has now become a successful and widely used medical material in various forms. The porcine small intestinal submucosa ECM (SIS-ECM) has been used as a supportive scaffold for healing in a variety of tissues, including arterial and venous tissues, tendons and wound closures 3 [1-4]. The porcine SIS-ECM consists of collagen, proteoglycan glycosaminoglycan, glycoprotein, and growth factors, and it has been approved as a commercial biomaterial for a variety of clinical applications [5,6]. However, the outcomes of its application are far from satisfactory; prominent noninfectious swelling and severe pain at the site of implantation often accompany its use because of the contamination of porcine DNA [7] and the Gal epitope, which both evoke immune responses [8].In general, matrix decellularization can be achieved by processing efforts; the side effects from using the SIS-ECM in clinical applications is approached based on the consequences of a deleterious innate antigen response.The α-Gal epitope is the chief antigen responsible for hyperacute rejection in xenotransplantation but there is a further non-Gal antigenicity concern. In vertebrates, glycans usually have terminal sialic acids that function as markers in normal cells and are recognized by a variety...

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Absence of Neu5Gc and Presence of Anti-Neu5Gc Antibodies in Humans—An Evolutionary Perspective

Cited by 79 publications

References 72 publications

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

Host Synthesized Carbohydrate Antigens on Viral Glycoproteins as “Achilles’ Heel” of Viruses Contributing to Anti-Viral Immune Protection

The Scaffold Derived from GGTA1 and CMAH Gene Knockout Pigs Generated by Gene Editing Provoked Little Inflammatory Responses in a Humanized Pig Model

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