Diversity in Rotavirus–Host Glycan Interactions: A “Sweet” Spectrum
2016; Elsevier BV; Volume: 2; Issue: 3 Linguagem: Inglês
10.1016/j.jcmgh.2016.03.002
ISSN2352-345X
AutoresSasirekha Ramani, Liya Hu, B. V. Venkataram Prasad, Mary K. Estes,
Tópico(s)Viral Infections and Immunology Research
ResumoInteraction with cellular glycans is a critical initial step in the pathogenesis of many infectious agents. Technological advances in glycobiology have expanded the repertoire of studies delineating host glycan–pathogen interactions. For rotavirus, the VP8* domain of the outer capsid spike protein VP4 is known to interact with cellular glycans. Sialic acid was considered the key cellular attachment factor for rotaviruses for decades. Although this is true for many rotavirus strains causing infections in animals, glycan array screens show that many human rotavirus strains bind nonsialylated glycoconjugates, called histo-blood group antigens, in a strain-specific manner. The expression of histo-blood group antigens is determined genetically and is regulated developmentally. Variations in glycan binding between different rotavirus strains are biologically relevant and provide new insights into multiple aspects of virus pathogenesis such as interspecies transmission, host range restriction, and tissue tropism. The genetics of glycan expression may affect susceptibility to different rotavirus strains and vaccine viruses, and impact the efficacy of rotavirus vaccination in different populations. A multidisciplinary approach to understanding rotavirus–host glycan interactions provides molecular insights into the interaction between microbial pathogens and glycans, and opens up new avenues to translate findings from the bench to the human population. Interaction with cellular glycans is a critical initial step in the pathogenesis of many infectious agents. Technological advances in glycobiology have expanded the repertoire of studies delineating host glycan–pathogen interactions. For rotavirus, the VP8* domain of the outer capsid spike protein VP4 is known to interact with cellular glycans. Sialic acid was considered the key cellular attachment factor for rotaviruses for decades. Although this is true for many rotavirus strains causing infections in animals, glycan array screens show that many human rotavirus strains bind nonsialylated glycoconjugates, called histo-blood group antigens, in a strain-specific manner. The expression of histo-blood group antigens is determined genetically and is regulated developmentally. Variations in glycan binding between different rotavirus strains are biologically relevant and provide new insights into multiple aspects of virus pathogenesis such as interspecies transmission, host range restriction, and tissue tropism. The genetics of glycan expression may affect susceptibility to different rotavirus strains and vaccine viruses, and impact the efficacy of rotavirus vaccination in different populations. A multidisciplinary approach to understanding rotavirus–host glycan interactions provides molecular insights into the interaction between microbial pathogens and glycans, and opens up new avenues to translate findings from the bench to the human population. SummaryRotaviruses exploit host glycans as receptors for cell attachment. The discovery that human rotaviruses bind a spectrum of host glycans provides new insights into virus pathogenesis. Glycan expression is determined genetically and regulated developmentally, which may affect susceptibility to infection and vaccination. Rotaviruses exploit host glycans as receptors for cell attachment. The discovery that human rotaviruses bind a spectrum of host glycans provides new insights into virus pathogenesis. Glycan expression is determined genetically and regulated developmentally, which may affect susceptibility to infection and vaccination. The surfaces of cells are decorated heavily with glycans or glycoconjugates, with structures ranging from simple monosaccharides to complex sugars with many different branches, linkages, and orientations.1Varki A. Sharon N. Historical background and overview.in: Varki A. Cummings R.D. Esko J.D. Essentials in glycobiology. 2nd ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2009: 1-22Google Scholar Interaction with host glycans is an essential and critical step in the infectivity of most, if not all, microbial pathogens. Many pathogens exploit these glycans for initial cell recognition and attachment, and for enteric viruses such as rotaviruses and noroviruses, these interactions are frequently the first critical step for initiation of infections. Key fundamental, clinical, and epidemiologic questions on rotavirus disease have been answered through studies on the interactions of rotavirus with host glycans. The approaches exemplify multidisciplinary translational science and involve virologists, structural biologists, glycobiologists, physicians, and epidemiologists (Figure 1). For example, screens using transformative new technologies in glycobiology such as glycan arrays identified histo-blood group antigens (HBGAs) as new glycan partners for human rotaviruses. These interactions were confirmed by enzyme-linked immunosorbent assays (ELISA) using synthetic glycans, and the basis of these interactions was elucidated using x-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. The biological relevance of these findings has been addressed using hemagglutination, saliva binding, and in vitro infectivity assays. Preliminary findings from cell lines now can be confirmed using physiologically relevant models of the human gut such as intestinal enteroids. Translational studies in people test if findings from the bench hold true at the bedside or at the population level. The findings from such team-science approaches not only have direct implications for our understanding of the biology of the virus, but also influence vaccine strategies, the development of therapeutics, and provide a new foundation for understanding other enteric infections. The diversity of glycans recognized by animal and human rotaviruses, insights gained into various aspects of viral pathogenesis such as interspecies transmission, host restriction, and tissue tropism, and the effect of genetic differences in glycan expression on susceptibility to infection and vaccination are reviewed here. Rotaviruses are the leading cause of severe dehydrating gastroenteritis in children younger than 5 years of age. Globally, rotavirus infections result in approximately 453,000 deaths each year, accounting for approximately 5% of child deaths.2Tate J.E. Burton A.H. 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The viral genome consists of 11 segments of double-stranded RNA that code for 6 structural viral proteins (VP) and 6 nonstructural proteins.17Estes M.K. Greenberg H.B. Rotaviruses.in: Knipe D.M. Howley P.M. Fields virology. 2. 6th ed. Kluwer/Lippincott, Williams and Wilkins, Philadelphia2013: 1347-1401Google Scholar The infectious virion is a triple-layered particle consisting of a core layer made of VP2, an intermediate layer made of VP6, and an outer shell made of glycoprotein VP7. Sixty protein spikes made of a protease-sensitive protein, VP4, extend from the VP7 shell (Figure 1, iv). Similar to the classification of influenza virus into H- and N- types based on the hemagglutinin and neuraminidase proteins, variability in the genes encoding the 2 rotavirus outer capsid proteins (VP7 and VP4) form the basis of a dual-nomenclature system used to classify rotaviruses into G and P genotypes, respectively. To date, 27 G genotypes and 37 P genotypes (Figure 2, dendrogram) have been identified.18Theuns S. Heylen E. Zeller M. et al.Complete genome characterization of recent and ancient Belgian pig group A rotaviruses and assessment of their evolutionary relationship with human rotaviruses.J Virol. 2015; 89: 1043-1057Crossref PubMed Scopus (40) Google Scholar As many as 70 different combinations of G and P genotypes have been described in human infections, although a vast majority are caused by G genotypes G1, G2, G3, G4, and G9, in combination with P genotypes P[4], P[6], and P[8]. Rotavirus replicates primarily in differentiated epithelial cells at the tips of the small intestinal villi. In animal models of rotavirus infection, histopathologic changes range from no or slight lesions such as enterocyte vacuolization, to major changes such as villous blunting and crypt hyperplasia.17Estes M.K. Greenberg H.B. Rotaviruses.in: Knipe D.M. Howley P.M. Fields virology. 2. 6th ed. Kluwer/Lippincott, Williams and Wilkins, Philadelphia2013: 1347-1401Google Scholar Pathogenesis is multifactorial. Rotavirus infection and a viral enterotoxin both alter intracellular calcium [Ca2+] signaling and stimulation of chloride [Cl-] secretion. Increased Ca2+ levels are thought to be central to stimulating Cl- secretion.17Estes M.K. Greenberg H.B. Rotaviruses.in: Knipe D.M. Howley P.M. Fields virology. 2. 6th ed. Kluwer/Lippincott, Williams and Wilkins, Philadelphia2013: 1347-1401Google Scholar Virus-mediated down-regulation of the expression of absorptive enzymes results in increased paracellular leakage through functional changes in the tight junctions between enterocytes.19Dickman K.G. Hempson S.J. Anderson J. et al.Rotavirus alters paracellular permeability and energy metabolism in Caco-2 cells.Am J Physiol Gastrointest Liver Physiol. 2000; 279: G757-G766PubMed Google Scholar, 20Tafazoli F. Zeng C.Q. 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Kovbasnjuk O. et al.Human enteroids as an ex-vivo model of host-pathogen interactions in the gastrointestinal tract.Exp Biol Med (Maywood). 2014; 239: 1124-1134Crossref PubMed Scopus (138) Google Scholar In addition, rotavirus infection results in a decrease in brush-border enzymes, such as sucrase isomaltase, leading to an osmotic gradient that can contribute to diarrhea.22Jourdan N. Brunet J.P. Sapin C. et al.Rotavirus infection reduces sucrase-isomaltase expression in human intestinal epithelial cells by perturbing protein targeting and organization of microvillar cytoskeleton.J Virol. 1998; 72: 7228-7236Crossref PubMed Google Scholar Villous ischemia and alterations in intestinal motility also have been reported in rotavirus infections,23Osborne M.P. Haddon S.J. Worton K.J. et al.Rotavirus-induced changes in the microcirculation of intestinal villi of neonatal mice in relation to the induction and persistence of diarrhea.J Pediatr Gastroenterol Nutr. 1991; 12: 111-120Crossref PubMed Scopus (35) Google Scholar with little or no evidence of inflammation. The attachment of the virus to epithelial cells is a multistep process involving the interaction of viral proteins with cellular receptors such as cell surface glycans.24Baker M. Prasad B.V. Rotavirus cell entry.Curr Top Microbiol Immunol. 2010; 343: 121-148PubMed Google Scholar The spike protein VP4 is implicated in the initial attachment to host cell glycans. During rotavirus infection, proteolysis results in the cleavage of the spike protein VP4 (88 kilodaltons) into VP5* (60 kilodaltons) and VP8* (28 kilodaltons) fragments that remain noncovalently attached to the virion (Figure 1, iv, inset).17Estes M.K. Greenberg H.B. Rotaviruses.in: Knipe D.M. Howley P.M. Fields virology. 2. 6th ed. Kluwer/Lippincott, Williams and Wilkins, Philadelphia2013: 1347-1401Google Scholar The binding to cellular glycans is mediated by the VP8* domain of VP4, whereas VP5* plays a role in host cell membrane penetration.25Denisova E. Dowling W. LaMonica R. et al.Rotavirus capsid protein VP5* permeabilizes membranes.J Virol. 1999; 73: 3147-3153Crossref PubMed Google Scholar, 26Dormitzer P.R. Sun Z.Y. Wagner G. et al.The rhesus rotavirus VP4 sialic acid binding domain has a galectin fold with a novel carbohydrate binding site.EMBO J. 2002; 21: 885-897Crossref PubMed Scopus (285) Google Scholar NMR and x-ray crystallography studies of VP8* from different rotavirus spike protein genotypes show that the protein exhibits a galectin-like fold with 2 twisted β-sheets separated by a shallow cleft (Figure 1, iv, inset).26Dormitzer P.R. Sun Z.Y. 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Hu L. et al.Structural basis of glycan interaction in gastroenteric viral pathogens.Curr Opin Virol. 2014; 7: 119-127Crossref PubMed Scopus (32) Google Scholar For more than 30 years, sialic acid (Sia) was considered the key determinant of interactions for rotavirus VP8*. This was based on early work showing that some rotavirus strains hemagglutinate red blood cells (RBCs) and that removal of terminal Sia residues by sialidase treatment of RBCs results in reduced virus binding.39Bastardo J.W. Holmes I.H. Attachment of SA-11 rotavirus to erythrocyte receptors.Infect Immun. 1980; 29: 1134-1140PubMed Google Scholar, 40Fiore L. Greenberg H.B. Mackow E.R. The VP8 fragment of VP4 is the rhesus rotavirus hemagglutinin.Virology. 1991; 181: 553-563Crossref PubMed Scopus (124) Google Scholar, 41Spence L. Fauvel M. 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Wagner G. et al.The rhesus rotavirus VP4 sialic acid binding domain has a galectin fold with a novel carbohydrate binding site.EMBO J. 2002; 21: 885-897Crossref PubMed Scopus (285) Google Scholar The rim of the groove is formed by side chains of Y188 and S190 on one side and Y155 on the other side, and the floor of the groove is formed by R101, V144, K187, and Y189 side chains. Key Sia binding residues R101, Y189, and S190 are strongly conserved among other sialidase-sensitive rotavirus strains. A similar Sia binding groove is present in the VP8* of a porcine P[7] rotavirus strain CRW-8 in complex with monosialodihexosylganglioside GM3.44Yu X. Coulson B.S. Fleming F.E. et al.Novel structural insights into rotavirus recognition of ganglioside glycan receptors.J Mol Biol. 2011; 413: 929-939Crossref PubMed Scopus (29) Google Scholar Although Sia binding is a common theme for the sialidase-sensitive animal rotavirus strains, there are variations in binding specificity to different members of the Sia family. The most common members of this family are N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc), which differ by the presence of an additional hydroxyl group in Neu5Gc. RRV VP8* shows greater affinity for Neu5Ac, and VP8* from bovine strain NCDV, porcine strains OSU and CRW-8, and simian strain SA11 show greater specificity for Neu5Gc.45Delorme C. Brussow H. Sidoti J. et al.Glycosphingolipid binding specificities of rotavirus: identification of a sialic acid-binding epitope.J Virol. 2001; 75: 2276-2287Crossref PubMed Scopus (127) Google Scholar, 46Dormitzer P.R. Sun Z.Y. 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Fleming F.E. et al.Structural basis of rotavirus strain preference toward N-acetyl- or N-glycolylneuraminic acid-containing receptors.J Virol. 2012; 86: 13456-13466Crossref PubMed Scopus (29) Google Scholar The binding of VP8* from many animal strains to Neu5Gc may be significant from an evolutionary perspective, given that Neu5Gc is expressed in mammalian tissues but not in normal human tissues. Binding to Neu5Gc is not described for any human rotavirus strain and correlates with the evolutionary loss of Neu5Gc expression in human beings.48Muchmore E.A. Diaz S. Varki A. A structural difference between the cell surfaces of humans and the great apes.Am J Phys Anthropol. 1998; 107: 187-198Crossref PubMed Scopus (146) Google Scholar The vast majority of strains causing human infections are insensitive to sialidase treatment.49Ciarlet M. Estes M.K. Human and most animal rotavirus strains do not require the presence of sialic acid on the cell surface for efficient infectivity.J Gen Virol. 1999; 80: 943-948Crossref PubMed Scopus (121) Google Scholar For P genotypes that are detected in both human beings and animals, sialidase sensitivity is VP4 genotype–specific and does not segregate by species of origin.50Ciarlet M. Ludert J.E. Iturriza-Gomara M. et al.Initial interaction of rotavirus strains with N-acetylneuraminic (sialic) acid residues on the cell surface correlates with VP4 genotype, not species of origin.J Virol. 2002; 76: 4087-4095Crossref PubMed Scopus (81) Google Scholar In the VP8* of prevalent P genotypes (P[4], P[6], and P[8] genotypes), as well as that of some other sialidase-insensitive strains, the key Sia binding residue R101 is replaced by amino acids with hydrophobic side chains that would prevent the formation of hydrogen bonds with Sia (Figure 2B).26Dormitzer
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