N-Glycolylneuraminic Acid in Animal Models for Human Influenza a Virus
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viruses Article N-Glycolylneuraminic Acid in Animal Models for Human Influenza A Virus Cindy M. Spruit 1 , Nikoloz Nemanichvili 2, Masatoshi Okamatsu 3, Hiromu Takematsu 4, Geert-Jan Boons 1,5 and Robert P. de Vries 1,* 1 Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands; [email protected] (C.M.S.); [email protected] (G.-J.B.) 2 Division of Pathology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands; [email protected] 3 Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Hokkaido, Japan; infl[email protected] 4 Department of Molecular Cell Biology, Faculty of Medical Technology, Graduate School of Health Sciences, Fujita Health University, 1-98 Dengakugakubo, Kutsukake, Toyoake 470-1192, Aichi, Japan; [email protected] 5 Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA * Correspondence: [email protected] Abstract: The first step in influenza virus infection is the binding of hemagglutinin to sialic acid- containing glycans present on the cell surface. Over 50 different sialic acid modifications are known, of which N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) are the two main species. Animal models with α2,6 linked Neu5Ac in the upper respiratory tract, similar to humans, are preferred to enable and mimic infection with unadapted human influenza A viruses. Animal models that are currently most often used to study human influenza are mice and ferrets. Citation: Spruit, C.M.; Nemanichvili, Additionally, guinea pigs, cotton rats, Syrian hamsters, tree shrews, domestic swine, and non-human N.; Okamatsu, M.; Takematsu, H.; primates (macaques and marmosets) are discussed. The presence of NeuGc and the distribution Boons, G.-J.; de Vries, R.P. N-Glycolylneuraminic Acid in of sialic acid linkages in the most commonly used models is summarized and experimentally Animal Models for Human Influenza determined. We also evaluated the role of Neu5Gc in infection using Neu5Gc binding viruses −/− A Virus. Viruses 2021, 13, 815. and cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) knockout mice, https://doi.org/10.3390/v13050815 which lack Neu5Gc and concluded that Neu5Gc is unlikely to be a decoy receptor. This article provides a base for choosing an appropriate animal model. Although mice are one of the most favored Academic Editor: Jessica A. Belser models, they are hardly naturally susceptible to infection with human influenza viruses, possibly because they express mainly α2,3 linked sialic acids with both Neu5Ac and Neu5Gc modifications. Received: 25 March 2021 We suggest using ferrets, which resemble humans closely in the sialic acid content, both in the Accepted: 28 April 2021 linkages and the lack of Neu5Gc, lung organization, susceptibility, and disease pathogenesis. Published: 1 May 2021 Keywords: influenza; animal model; N-glycolylneuraminic acid; N-acetylneuraminic acid; CMAH; Publisher’s Note: MDPI stays neutral sialic acid linkage; mouse; ferret with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Infection of humans by influenza A viruses starts at the epithelium cells in the upper respiratory tract, where the hemagglutinin (HA) on the outside of a virus particle binds to Copyright: © 2021 by the authors. α Licensee MDPI, Basel, Switzerland. glycans with a terminal sialic acid. The terminal sialic acids can be linked through an 2,3 α α This article is an open access article or 2,6 bond to the penultimate galactose. In humans, mainly 2,6 linked sialic acids are distributed under the terms and present in the upper respiratory tract. The expression of α2,3 and α2,6 linked sialic acids conditions of the Creative Commons varies between species and tissues [1]. Attribution (CC BY) license (https:// Another variable in the influenza receptor is the type of sialic acid, of which N- creativecommons.org/licenses/by/ acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) are the main 4.0/). species (Figure1). The majority of influenza A viruses use a glycan with a terminal Viruses 2021, 13, 815. https://doi.org/10.3390/v13050815 https://www.mdpi.com/journal/viruses Viruses 2021, 13, 815 2 of 17 Viruses 2021, 13, 815 2 of 17 species (Figure 1). The majority of influenza A viruses use a glycan with a terminal Neu5AcNeu5Ac as as their their receptor, receptor, although somesome strainsstrains useuse Neu5GcNeu5Gc instead instead [ 2[2,3],3]. Importantly,. Importantly, onlyonly Neu5Ac Neu5Ac isis presentpresent in in humans humans [4 –[46].–6 Human]. Human influenza influenza A viruses A viruses specifically specifically bind α 2,6bind αlinked2,6 linked sialic sialic acids. acids. FigureFigure 1. 1. StructureStructure of of N N-acetylneuraminic-acetylneuraminic acid (Neu5Ac) andand N-glycolylneuraminicN-glycolylneuraminic acid acid (Neu5Gc). (Neu5Gc). Neu5Gc can be produced in animals that express an active form of the enzyme Neu5Gc can be produced in animals that express an active form of the enzyme cyti- cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH), which facilitates dinethe hydroxylationmonophosphate of Neu5Ac-N-acetylneuraminic to turn it into Neu5Gc.acid hydroxyla However,se the(CMAH), gene encoding which facilitates CMAH, themainly hydroxylation expressed of in Neu5Ac mammalian to turn species, it into has Neu5Gc. been lost However, partially the or gene completely encoding in several CMAH, mainlyevents expressed during evolution in mammalian [4]. Possibly, species, the has negative been selectionlost partially of Neu5Gc or completely was induced in several by eventslethal pathogensduring evolution binding [4] to. Neu5Gc. Possibly, Therefore, the negative the lossselection of Neu5Gc of Neu5Gc protected was individuals induced by lethalfrom pathogens infection with binding these to pathogens Neu5Gc. Therefore, [7]. The presence the loss of of Neu5Gc an intact protected CMAH geneindividuals does fromnot automatically infection with lead these to highpathogens expression [7]. The of Neu5Gc presence in of all an tissues intact [ 8CMAH]. The expression gene does ofnot automaticallyNeu5Gc in species lead usedto high as animal expression models of for Neu5Gc human influenzain all tissues has received [8]. The little expression attention of Neu5Gcso far and in nospecies clear used overview as animal of this models expression for human is available. influenza has received little attention so farProper and no animal clear overview models are of essentialthis expression for fundamental is available. and applied research on human influenzaProper viruses, animal vaccines, models andare essential antivirals. for Often fundamental considered and factors applied for choosing research an on animal human influenzamodel are viruses, the experimental vaccines, and costs, antivirals. disease Often pathogenesis, considered and factors susceptibility. for choosing Currently, an ani- malthe model sialic acid are linkagethe experimental and especially costs, the disease Neu5Gc pathogenesis, content are oftenand susceptibility. overlooked. Human Currently, in- thefluenza sialic virusesacid linkage mainly and bind especiallyα2,6 linked the Neu5Gc Neu5Ac, content while many are often animal overlooked. models express Human influenzaNeu5Gc. Theviruses lack mainly of correct bind sialic α2,6 acid linked receptors Neu5Ac, in animal while models many could animal skew models the results express of Neu5Gc.a study since The adaptationlack of correct of a sialic virus mayacid bereceptors required in before animal a successfulmodels could infection skew is the possible. results ofThe a study animal since models adaptation mostly used of a virus to study may human be required influenza befo arere ferrets a successful (Mustela infection putorius is furo pos-) and mice (Mus musculus). While ferrets mainly express the human receptor (α2,6 linked sible. The animal models mostly used to study human influenza are ferrets (Mustela Neu5Ac), mice also express Neu5Gc and the sialic acid linkages in the respiratory tract dif- putorius furo) and mice (Mus musculus). While ferrets mainly express the human receptor fer from humans [1,6,9–19]. Other animal models that are discussed in this article are cotton (α2,6 linked Neu5Ac), mice also express Neu5Gc and the sialic acid linkages in the respir- rats (Sigmodon species), Syrian hamsters (Mesocricetus auratus), guinea pigs (Cavia porcellus), atory tract differ from humans [1,6,9–19]. Other animal models that are discussed in this domestic swine (Sus scrofa domesticus), macaques (Macaca), and marmosets (Callitrichidae). articleOf these are animals, cotton rats domestic (Sigmodon swine species), are naturally Syrian infected hamsters by human (Mesocricetus influenza auratus viruses), guinea [1]. pigs (InCavia this porcellus article, we), domestic summarize swine the current(Sus scrofa knowledge domesticus) on, Neu5Gc macaques expression (Macaca in), and animal mar- mosetsmodels (Callitrichidae for human influenza). Of these and animals, supplement domestic this swine with protein are naturally histochemistry infected stainsby human on influenzalung tissues. viruses The [1] role. of Neu5Gc in influenza virus infection is still unclear. Furthermore, studiesIn this on Neu5Gcarticle, we specific summarize influenza the virusescurrent