Receptor for influenza virus

Fig. 4—A comparison of the H-D antigenic component and the receptor for influenza virus hemagglutinin, which are a-NeuGc-(2 — 3)-/ -Gal and a-NeuAc-(2 — 3)-/ -Gal, respectively, on the backbones / -D-Gal-( 1 — 4)-jS-d-G1cNAc-( 1 -> 3)-jS-D-Gal-(l - 4)-d-G1cNAc (sialyl i), yS-D-Gal-(l — 4)-yJ-D-GlcNAc-(l - 6)-D-Gal (sialyl I). The CH3 of the acetamido group of Ar-acetylneuraminic acid, which is a CH2OH group in iV-glycolyl-neuraminic acid, is shown.

If all the sugar residues of the glycophorin molecules in an erythrocyte were spread over the surface of the cell they could cover approximately one-fifth of its surface in a loose network. However, it is more likely that they form bushy projections of a more localized sort. These oligosaccharides not only act as immunological determinants but also serve as receptors for influenza viruses. Other glycoproteins related to glycophorin A occur in smaller amounts.244... 

A comparative immunochemical study of human erythrocyte membrane glycoprotein which uses two different extraction procedures has been reported. Each preparation contained receptors for influenza virus and was composed of protein (50%) and carbohydrate (30—40%). 

Though the role of A-acetylneuraminic acid as a receptor determinant for influenza virus has been known for 40 years, the actual receptor used by this virus to infect cells has not been identified unequivocally. As sialic acid is a frequent sugar on glycoproteins and glycolipids of vertebrate cells, most surface components contain A-acetylneuraminic acid or a derivative of it. All sialylated molecules present on the cell surface are potential receptors for influenza viruses or paramyxoviruses provided they contain sialic acid according to the requirements discussed above (Section 4.1). In the case of erythrocytes, the majority of the surface-bound sialic acid is present on glycophorin. Following isolation from... 

In general, virus receptors carry out normal functions in the cell. For example, in bacteria some phage receptors are pili or flagella, others are cell-envelope components, and others are transport binding proteins. The receptor for influenza vims is a glycoprotein found on red blood cells and on cells of the mucous membrane of susceptible animals, whereas the receptor site of poliovirus is a lipoprotein. However, many animal and plant viruses do not have specific attachment sites at all and the vims enters passively as a result of phagocytosis or some other endocytotic process. 

In concurrent investigations with R. Brossmer, crystalline 3 -0-(N-acetylneuraminyl)lactose was isolated from cow colostrum and demonstrated to be a substrate for influenza virus enzyme and for the receptor-destroying enzyme of Vibrio cholerae. The structure of N-acetylneuraminic acid, then still a matter of contention, was clarified by chemical degradation, and the configuration at C-4 that had remained unknown was established. Finally, the acid was synthesized in good yield (with G. Baschang). 

The recognition of a ligand by a membrane-associated receptor or an enzyme (covalently or non-covalently incorporated into the PDA scaffold) provides die needed driving force to induce chromatic transition of PDA upon Ae occurrence of the interfacial binding event (i.e., biochromism), leading to die birdi of colorimetric biosensors for influenza virus, bacterial toxins and E. coli (4-6). 

Glycolipids are potential receptors also for influenza viruses (Suzuki et al., 1986 Herrler and Klenk, 1987). As discussed above, glycoproteins may function as alternative receptors. Cells that are resistant to infection by influenza C virus because of a lack of receptors, have been shown to become susceptible to infection if they are resialylated with 9-0-acetylated sialic acid (Szepanski et al., 1992). As the a2,6-sialyltransferase used attaches sialic acid specifically to oligosaccharides present on glycoproteins, the virus obviously used glycoprotein receptors to infect these cells. The same approach has been applied to influenza A virus. In this case, cells were pretreated with sialidase to inactivate endoge-... 

Matrosovich M, Klenk H-D (2003) Natural and synthetic sialic acid-containing inhibitors of influenza virus receptor binding. Rev Med Virol 13 85-97 Matrosovich MN, Matrosovich TY, Gray T, Roberts NA, Klenk H-D (2004) Neuraminidase is important for the initiation of influenza virus infection in human airway epithelium. J Virol 78 12665-12667... 

Glycophorin A appears to serve a variety of functions on the red-cell membrane, and has been implicated in several red-cell disorders. Because it extends from the external environment of the cell into the cell cytoplasm, it is considered to constitute a receptor for malarial parasites,"" influenza viruses, lectins, and Portuguese man-of-war toxin. Many of these receptor functions are attributable to the carbohydrate composition of these... 

The initial step in the sequence of events leading to influenza virus infections in mammalian hosts is mediated by the multiple attachment of virus particles to host sialoside receptors in the nasopharynx [41]. These receptors consist largely of cell surface sialylated glycoproteins and gangliosides. The subsequent steps involve receptor-mediated endocytosis with ensuing release of the viral nucleo-plasmid. The first event responsible for the receptor-virus interaction is therefore an attractive target for both antiviral and related microbial intervention. 

Influenza virus particles are spheroidal and approximately 100 nm in diameter. The outer-membrane envelope contains 500 copies of hemagglutinin (HA) trimers and 100 copies of neuraminidase tetramers. The hemagglutinin constitutes the receptor sites for a-sialoside ligands. X-ray analyses show that the three sialic acid binding pockets reside 46 A apart, each trimer being separated on the virion surface by about 65-110 A [42],... 

Fig. 8 (top) Liposome with polydiacetylene linked monolayer mixed with ligand for receptor detection. (bottom) Colorimetric detection of influenza virus using polymerized liposomes to which have been added increasing amounts of influenza virus from left to right. [18]... 

Recent publications signal the continued interest in the function of this protein. It has been called a stress enzyme, involved in influenza virus infection (Tomas and Toparceanu, 1986). An explanation for Wilson s disease in terms of a genetic defect resulting in failure to convert from a neonatal (i.e., low) level of ceruloplasmin and copper to a normal adult level has been reported (Srai et al., 1986). Tissue specificity for the binding of ceruloplasmin to membranes was demonstrated in a study investigating the possible role of ceruloplasmin-specific receptors in the transfer of copper from ceruloplasmin to other copper-containing proteins (Orena et al, 1986). Ceruloplasmin has been shown to be effective in transferring copper to Cu,Zn-SOD in culture (Dameron and Harris, 1987), as has copper albumin. In view of the variable content of copper in this protein, it is not clear which copper is transferred. 

Polythiophenes functionalized with monosaccharides have been evaluated for their ability to detect the influenza virus and E. coli (Baek et al. 2000). Copolymers of thiophene acetic acid 10 and carbohydrate-modified thiophenes 11 have been prepared via iron(III) chloride mediated polymerization. Addition of influenza virus to a sialic acid containing copolymer resulted in a blue shift of the polymer absorption maximum, resulting in an orange to red chromatic transition. Mannose-containing polythiophenes underwent color changes upon the addition of the lectin ConA or E. coli cells that contain cell surface mannose-binding receptors. A similar biotinylated pol5hhiophene afforded a streptavidin responsive material (Paid and Leclerc 1996). 

Interestingly, erythrocytes that had lost (2—>3)-sialyl residues were still agglutinable by influenza viruses.531 In similar experiments with Madin-Darby, bovine kidney-cells and Sendai viruses, (2— 3)-sialyl residues as components of the oligosaccharide sequence a-Neu5Ac-(2— 3)-/3-Gal-(T 3)-GalNAc constitute specific receptors for these... 

There is a wide variety of vectors used to deliver DNA or oligonucleotides into mammalian cells, either in vitro or in vivo. The most common vector systems are based on viral [retroviruses (9, 10), adeno-associated virus (AAV) (11), adenovirus (12, 13), herpes simplex virus (HSV) (14)] andnonviral [cationic liposomes (15,16), polymers and receptor-mediated polylysine-DNA] complexes (17). Other viral vectors that are currently under development are based on lentiviruses (18), human cytomegalovirus (CMV) (19), Epstein-Barr virus (EBV) (20), poxviruses (21), negative-strand RNA viruses (influenza virus), alphaviruses and herpesvirus saimiri (22). Also a hybrid adenoviral/retroviral vector has successfully been used for in vivo gene transduction (23). A simplified schematic representation of basic human gene therapy methods is described in Figure 13.1. 

---