N-Glycolylneuraminic Acid (Neu5Gc) Null Large Animals by Targeting the CMP-Neu5Gc Hydroxylase (CMAH).

Andrea Perota,Cesare Galli

doi:10.3389/fimmu.2019.02396

Abstract

The two major sialic acids described in mammalian cells are the N-glycolylneuraminic acid (Neu5Gc) and the N-acetylneuraminic acid (Neu5Ac). Neu5Gc synthesis starts from the N-acetylneuraminic acid (Neu5Ac) precursor modified by an hydroxylic group addition catalyzed by CMP-Neu5Ac hydroxylase enzyme (CMAH). In humans, CMAH was inactivated by a 92 bp deletion occurred 2–3 million years ago. Few other mammals do not synthetize Neu5Gc, however livestock species used for food production and as a source of biological materials for medical applications carry Neu5Gc. Trace amounts of Neu5Gc are up taken through the diet and incorporated into various tissues including epithelia and endothelia cells. Humans carry “natural,” diet-induced Anti-Neu5Gc antibodies and when undertaking medical treatments or receiving transplants or devices that contain animal derived products they can cause immunological reaction affecting pharmacology, immune tolerance, and severe side effect like serum sickness disease (SSD). Neu5Gc null mice have been the main experimental model to study such phenotype. With the recent advances in genome editing, pigs and cattle KO for Neu5Gc have been generated always in association with the αGal KO. These large animals are normal and fertile and provide additional experimental models to study such mutation. Moreover, they will be the base for the development of new therapeutic applications like polyclonal IgG immunotherapy, Bioprosthetic Heart Valves, cells and tissues replacement.

Highlights

Sialic acids are monosaccharide expressed on the cell surface
The continuous exposure to Neu5Gc residues, present in the diet through products of animal origin or used as vital supports in various medical treatments, may theoretically result in a state of persistent inflammation tentatively called “xenosialitis.” This condition has been proposed as an explanation of various diseases that characterize our species, despite the elimination of the Neu5Gc antigen and the development of Anti-Neu5Gc antibodies in humans having been an evolutionarily advantage in resisting to pathogens [66]
Further studies are needed to assess the eventual susceptibility of Pigs and Cattle lacking Neu5Gc to human pathogens like for example Influenza A Virus (IAV)

Summary

Introduction

Sialic acids are monosaccharide expressed on the cell surface. They are incorporated as terminal residues in different types of glycoproteins and glycolipids. The possibility that diet induced Anti-Neu5Gc antibodies could have pathological effects in vascular diseases or oncogenesis is still debated in humans, there is evidence for the role of Anti-Neu5Gc in rejection of animal derived tissues [see Salama et al for review [14]].

Results

Conclusion