To trace the evolutionary path of these new pathogens, we performed a selectionpressure analysis of a large number of hemagglutinin ha and neuraminidase na gene sequences of h1n1 influenza viruses from different hosts. Among the avian influenza viruses, two eurasian viruses, h5n1 and h7n9, are unique in producing human infections and fatalities. As was mentioned before, hemagglutinin neuraminidase hn protein is a combination of two proteins in mumps virus that are similar to those in influenza but are separated in this case. Initiation of virus infection involves multiple has binding to sialic acids on carbohydrate side chains of cellsurface glycoproteins and glycolipids 4 6. The interplay between the host receptor and influenza virus hemagglutinin and neuraminidase article pdf available in international journal of molecular sciences 187. Comparison of hemagglutinin and neuraminidase of influenza a virus subtype h1n1, h5n1, h5n2 and h7n9 using apriori algorithm. Pdf the structure, function, and inhibition of influenza. Persistence of antibodies to influenza hemagglutinin and. The influenza virus major surface glycoproteins, hemagglutinin ha, and.
Neuraminidase na is the second major surface protein of influenza a and b viruses. Neuraminidases cleave the terminal sialic acid residues from carbohydrate chains in glycoproteins. Haemagglutinin ha and neuraminidase na are two vital surface glycoproteins of. The role of hemagglutinin and neuraminidase in influenza. Hemagglutininneuraminidase refers to a single viral protein that has both hemagglutinin and endo neuraminidase ec 3. Additionally, hemagglutinin ha, when treated with exogenous neuraminidase na or coexpressed with viral na, could be released from cells independently of m1. Recently, two more ha were discovered exclusively in bats h17 and h18 7. Pdf influenza a virus hemagglutinin and neuraminidase. Sialic acid is a negatively charged sugar associated with the protein and lipid portions. All but h17n10 and h18n11 subtypes, found to date in peruvian bats , 14, circulate in wild aquatic birds, which is by far the largest of the known natural iav reservoirs, which also include humans, swine, horses, dogs, and seals. Neuraminidase, also called sialidase, any of a group of enzymes that cleave sialic acid, a carbohydrate occurring on the surfaces of cells in humans and other animals and in plants and microorganisms. The process of the rbcs agglutinating is called hemagglutination or haemagglutination. Influenzahemagglutininand neuraminidasemembrane glycoproteins.
Molecular characterization of hemagglutininneuraminidase. Member viruses of the family paramyxoviridae are enveloped, 150 to 300 nm in diameter, ranging in shape from spherical to almost filamentous. The structural basis for these diverse functions remains to be fully understood. Aoki, in mandell, douglas, and bennetts principles and practice of infectious diseases eighth edition, 2015. Jardetzkya,2 adepartment of structural biology, stanford university school of medicine, stanford, ca 94305. Examples of zoonotic influenza include avian influenza, also known as bird flu, with virus subtypes ah5n1 and ah9n2, and swine influenza, also known as swine flu, with virus subtypes ah1n1 and ah3n2. In the 1940s american scientist george hirst identified in samples of influenza virus mixed with red blood cells erythrocytes a substance that broke down receptors on the surfaces of red cells. The viral neuraminidases are frequently used as antigenic. Van poucke s, doedt j, baumann j, qiu y, matrosovich t, klenk hd, et al. The paramyxovirus hemagglutinin neuraminidase hn functions in virus attachment to cells, cleavage of sialic acid from oligosaccharides, and stimulating membrane fusion during virus entry into cells. Polypeptides, polynucleotides, methods, compositions, and vaccines comprising influenza hemagglutinin and neuraminidase variants are provided. Influenza b viruses with mutation in the neuraminidase active.
Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell. Influenza neuraminidase cleaves terminal sialic acid residues on glycoconjugates and destroys the receptors recognized by viral. Us20050042229a1 influenza hemagglutinin and neuraminidase. The 2nd sialic acidbinding site of influenza a virus neuraminidase. This is in contrast to the proteins found in influenza, where both functions exist but in two separate proteins. Eighteen hemagglutinin and 11 neuraminidase subtypes are known to exist in nature. These viruses present two major surface glycoproteins. Glycosylation of haemagglutinin and stalklength of neuraminidase combine to regulate. Influenza a virus hemagglutinin neuraminidasereceptor balance. Hemagglutininneuraminidase an overview sciencedirect. Hemagglutinin ha is the viral protein that facilitates the entry of influenza viruses into host cells. Hemagglutininneuraminidase an overview sciencedirect topics. As with hemagglutinin, neuraminidase comes in a variety of subtypes named n1n9. Membrane fusion commences from inside the endosome after a.
Human and swine influenza are sometimes caused by type a. There are 9 different forms of neuraminidase, designated n1 through n9, that are associated with influenza type a viruses. The hemagglutinin and neuraminidase genes encode for two surface proteins and are used in the analysis of genetic variability. Influenza virus attaches itself to sialic acids on the surface of epithelial cells of the upper respiratory tract of the host using its own protein hemagglutinin. The two glycoproteins of the influenza virus membrane, hemagglutinin ha 3 and neuraminidase na, both recognize sialic acid 1, 3. Influenza virus hemagglutinin cleavage into ha1, ha2. Hemagglutinin neuraminidase balance confers respiratorydroplet transmissibility of the pandemic h1n1 in. Wo206144a2 influenza hemagglutinin and neuraminidase. What is the function of hemagglutinin and neuraminidase. Incorporation of m1 into vlps required ha expression, although when m1 was omitted from vlps, particles with morphologies similar to those of wildtype vlps or viruses were observed. Mar 27, 2017 influenza a virus iav membrane proteins hemagglutinin ha and neuraminidase na are determinants of virus infectivity, transmissibility, pathogenicity, host specificity, and major antigenicity. Attaches the virus to sialic acidcontaining cell receptors and thereby initiating infection.
Only the hemagglutinin, neuraminidase, and basic polymerase 1 genes from the avian gene pool have entered the human population by reassortment, leading to the 1957 h2n2 and 1968 h3n2 pandemics. It plays a key role at the final stage of infection by removing terminal sialic acid moieties from hostcell. Neuraminidase sialidase enzymes are glycoside hydrolase enzymes that cleave cut the glycosidic linkages of neuraminic acids. Toconfirm this assumption and to identifythe genescoding for neuraminidase, we compared the rnapatterns of the. In molecular biology, hemagglutinin or haemagglutinin british english. Biological property of recombinant hemagglutininneuraminidase protein of avian paramyxovirus type 6 expressed by recombinant baculovirus jiye kim1, hyunjeong lee1, soojeong kye2, saeromi kim1, heejung seul1, sangeun kim4, heesoo lee3, sukchan jung1 and kangseuk choi1. The interplay between the host receptor and influenza virus hemagglutinin and neuraminidase. Neuramidase is needed to remove the acid from the cell and to allow the recently synthesized virus to sprout and invade the next cell. Functional balance between neuraminidase and haemagglutinin in. Neuraminidase inhibitor an overview sciencedirect topics. Hemagglutinin ha is a transmembrane protein of the influenza a virus and a key component in its life cycle. Role of neuraminidase in lethal synergism between influenza virus and streptococcus pneumoniae. The ha and neuraminidase na glycoproteins are the 2 major surface antigens of the influenza virus and facilitate infection.
The envelope contains two major glycoproteins present as 8 to 14 nm spikelike projections. This protein controls two critical aspects of entry. Neuraminidase inhibitor resistance in vitro results from mutations in the viral hemagglutinin andor neuraminidase. Since its emergence in march 2009, the pandemic 2009 h1n1 influenza a virus has posed a serious threat to public health. Expression of functional recombinant hemagglutinin and. Importance of neuraminidase activesite residues to the neuraminidase inhibito r resistance of in uenza viruses. Virus hemagglutinin an overview sciencedirect topics.
Sequence similarities for ha1 are 58% between h1 and h5, 46% to 48% between. A nanomolar multivalent ligand as entry inhibitor of the. Influenza hemagglutinin and neuraminidase membrane glycoproteins. Positive selection on hemagglutinin and neuraminidase genes. We concluded that cooperation of ha and na moves iav particles on a cell surface and enhances virus infection of host cells. Influenza a virus iav membrane proteins hemagglutinin ha and neuraminidase na are determinants of virus infectivity, transmissibility, pathogenicity, host. Phylogenetic analysis of hemagglutinin and neuraminidase genes of highly pathogenic avian influenza h5n1 egyptian strains isolated from 2006 to 2008 indicates.
Influenza virus continues to have a major impact on global health and is responsible for millions of cases of respiratory illness and hundreds of thousands of hospitalizations annually in the united states alone. Neuraminidase hemagglutinin abstract practical methods to measure the potency of in. Vaxarray for hemagglutinin and neuraminidase potency testing. In chick embryo cells infected with a mesogenic ndv strain beaudette both activities undergo a sharp decrease, whereas after infection with a velogenic strain. Influenza a virus hemagglutinin and neuraminidase act as. Influenza virus neuraminidase structure and functions.
We report the crystal structures of the parainfluenza virus 5 sv5 hn and its complexes with sialic acid, the. The protein allows the virus to enter a host cell by recognizing specific glycans attached to transmembrane proteins of the host, which leads to viral endocytosis. Influenza virus neuraminidase structure and functions ncbi. Study of immunogenicity of recombinant proteins based on hemagglutinin and neuraminidase conservative epitopes of influenza a virus. Related hes occur in influenza c, toro, and coronaviruses, apparently as a result of relatively recent lateral gene transfer events. A computational assay that explores the hemagglutinin neuraminidase. Hes is a dimer transmembrane protein consisting of two monomers, each monomer. A computational assay that explores the hemagglutinin. Crystal structure of the multifunctional paramyxovirus hemagglutininneuraminidase article pdf available in nature structural biology 711.
These subtypes are defined by their interaction with antibodies. These vaccines have long been evaluated based on the antibody response they elicit, particularly to the viral hemagglutinin ha 1, 2. Initiation of virus infection involves multiple has binding to sialic acids on carbohydrate side chains of cellsurface glycoproteins and glycolipids 4, 6. Competitive cooperation of hemagglutinin and neuraminidase. The envelope encloses a helical nucleocapsid structure containing the viral rna genome.
Binding of hn protein to the receptor induces a conformational change that allows the f protein to trigger virioncell membranes fusion by similarity. Hemagglutinin and neuraminidase sequences in the 2007 2008 trivalent vaccine showing identified sequence in bold red. Early alterations of the receptorbinding properties of h1, h2. To design the amplification of hemagglutinin and neuraminidase genes, we used bioinformatic tools and polimerase chain reaction. A longheld dogma posits that strong presentation to the immune system of the dominant influenza virus glycoprotein antigens neuraminidase na and hemagglutinin ha is paramount for inducing protective immunity against influenza virus infection. Deliberate reduction of hemagglutinin and neuraminidase.
Haemagglutinin ha and neuraminidase na are the two most prominent surface glycoproteins of iav, and are commonly used as the primary immunogenic components of current influenza vaccines 5,6. Interaction of the m1 protein with the viral hemagglutinin ha or neuraminidase na glycoprotein was extensively analyzed by using wildtype and transfectant influenza viruses as well as recombinant vaccinia viruses expressing the m1 protein, ha, or na. Jun 05, 2010 what is the function of hemagglutinin and neuraminidase. The appropriate combination of hemagglutinin and neuraminidase. Although the influenza a virus surface glycoprotein neuraminidase na.
Mumps virus hemagglutinin neuraminidase protein proteopedia. Neuraminidases are enzymes that cleave sialic acid groups from glycoproteins and are required for influenza virus replication. May 24, 2002 hemagglutinin neuraminidase hn protein, which is responsible for virus attachment, interacts with the fusion protein in a virus typespecific manner to induce efficient membrane fusion. Hemagglutinin is a class i fusion protein, having multifunctional activity as both an attachment factor and membrane fusion protein. The hemagglutinin esterases hes are a family of viral envelope glycoproteins that mediate reversible attachment to oacetylated sialic acids by acting both as lectins and as receptordestroying enzymes rdes.
Figure 2structure of hemagglutinin ha and neuraminidase na. Glycosylation of haemagglutinin and stalklength of neuraminidase combine to. Influenza a virus hemagglutininneuraminidasereceptor balance. The threedimensional structure of the haemagglutinin neuraminidase hn from a human parainfluenza virus is described at ca 2. Note that agglutination is one of three steps in the more complex process of coagulation. Here we use it to produce correctly folded and glycosylated versions of the influenza a virus surface glycoproteins the hemagglutinin ha and the neuraminidase na. These are small changes or mutations in the genes of influenza viruses that can lead to changes in the surface proteins of the virus. The high variability of the influenza virus genome is reflected by a wide spectrum in host tropism, tissue specificity, and pathogenicity, ranging from local infection of the respiratory tract or the gut, as is the case with most mammalian strains and the apathogenic avian viruses, to systemic infection caused by fowl plague virus or other highly pathogenic avian strains. Hemagglutinin esterase hes is a glycoprotein that certain enveloped viruses possess and use as invading mechanism. Species specificity of influenza virus is determined by the linkages of the sialic acids. Following virus replication, the receptordestroying enzyme, na, removes its. We have analyzed the mechanism by which the matrix m1 protein associates with cellular membranes during influenza a virus assembly. Hemagglutininneuraminidase hn protein, which is responsible for virus attachment.
Structural studies of the parainfluenza virus 5 hemagglutinin. The bestknown neuraminidase is the viral neuraminidase, a drug target for the prevention of the spread of influenza infection. To elucidate the mechanism of hnpromoted membrane fusion, we characterized a series of newcastle disease virus hn proteins whose surface residues were mutated. Structure of the newcastle disease virus hemagglutinin neuraminidase hn ectodomain reveals a fourhelix bundle stalk ping yuana, kurt a. A hemagglutinin ha genes and b neuraminidase na genes. Amino acids of hemagglutinin and neuraminidase that. Hn hemagglutininneuraminidase newcastle disease virus. Hemagglutinin ha and neuraminidase nase activities accumulated in cells infected with different myxoviruses respond to the treatment of cells with cycloheximide in different ways. Hemagglutinin ha and neuraminidase na hemagglutinin designated as ha and neuraminidase designated as na are glycoproteins. Neuraminidase enzymes are a large family, found in a range of organisms. Influenza vaccines are the best tool currently available to reduce the risk of influenza infection and associated complications. Amino acids of hemagglutinin and neuraminidase that provoke humantohuman infection in avian influenza virus. As an example, we chose the ha and na proteins expressed by the novel h7n9 virus that recently emerged in china.
Hemagglutinin and neuraminidase volume 24, number 10october 2018 emerging infectious diseases journal cdc volume 24, number 10october 2018. We have deliberately violated this dogma by constructing a recombinant influenza virus strain of apr834 h1n1 in which expression of na. Influenza hemagglutinin and neuraminidase variants download pdf info publication number us20050042229a1. N glycosylation sites are highlighted in green, as determined by incorporation of 18o during enzymatic deglycosylation with pngase f. In addition, influenza a zoonotic viruses are a constant pandemic threat. Phylogenetic analysis of hemagglutinin and neuraminidase.
Occurence of unstability of hemagglutinin and neuraminidase. The two glycoproteins of the influenza virus membrane, hemagglutinin ha 3 and neuraminidase na, both recognize sialic acid 1 3. Hemagglutinin is a protein that binds tightly to the sugar portions of various cellsurface glycoproteins by recognizing and binding the sugar sialic acid, which is also called nacetyl neuraminic acid. The envelope glycoproteins, hemagglutinin ha and neuraminidase na, mediate host cell attachment and release, respectively, and are the primary targets of the protective antibody. Oseltamivir is 1 of 2 antiviral medications available for the treatment of influenza b virus infections. Structure of coronavirus hemagglutininesterase offers. One way influenza viruses change is called antigenic drift. Hes helps in the attachment and destruction of certain sialic acid receptors that are found on the host cell surface. These subtypes are one of the causes of the continual effectiveness of influenza. Its neuraminidase domain has the cazy designation glycoside hydrolase family 83 gh83 it does show a structural similarity to influenza viral. Structure of the newcastle disease virus hemagglutinin. In a series of experiments confirming and synthesizing 25 years of experimental data 24, goto and kawaoka 1 demonstrate specifically how the neuraminidase na protein of influenza awsn33 h1n1, a curious variant of the first human influenza virus ever isolated, mediates hemagglutinin ha cleavage. We describe and characterize a cluster of influenza b viruses circulating in north carolina with a mutation in the neuraminidase active site that may reduce susceptibility to oseltamivir and the investigational drug peramivir but not to zanamivir.
Mitnaul lj, matrosovich mn, castrucci mr, tuzikov ab, bovin nv, kobasa d, kawaoka y. Pdf study of immunogenicity of recombinant proteins. The nterminal hydrophobic transmembrane domain, however, contains a variable sequence of amino acids spanning residues 729 and. Therefore, ha is responsible for binding influenza virus to sialic acid on the surface of target cells, such as cells in the upper respiratory tract or erythrocytes, 1 causing as a result the internalization of. In order for ha to carry out these functions, it must first undergo a priming step, proteolytic cleavage, which renders it fusion competent. Influenza a virus hemagglutinin and neuraminidase act as novel. Together with various forms of hemagglutinin, neuraminidase is used to distinguish between subtypes of influenza a viruses e. Hn hemagglutininneuraminidase human parainfluenza 1. Forrest d, angela ferguson, katim choya, jeremy jonesd, diana dikyan wonga, peter pakhang cheunga, chehsiung hsuc, olive t. N1 neuraminidase acalifornia h1n1 1 tffltqgallndk, 2 yngiitdtik, 3 ygngvwigr, 4 gdvfvir h3 hemagglutinin avictoria h3n2 1 idlwsynaellvalenqhtidltdsemnk, 2 stqaaidqingk, 3 sqqavipnigfrpr, 4 lnwlthlnfk n2 neuraminidase avictoria h3n2 1 tllmnelgvpfhlgtk, 2 lvdsvvswsk, 3 sgysgifsvegk, 4 gwafddgndvwmgr hb hemagglutinin. Sep 10, 2009 neuraminidase na recognizes the same molecule as hemagglutinin, sialic acid of the cell membrane, but it performs its function in an opposite way, its role is to help the virus to leave the invaded cell. Recall that the surface of the influenza virion is covered with spikes of hemagglutinin and neuraminidase. About europe pmc funders joining europe pmc governance roadmap outreach.
A glycoprotein is a protein that contains a short chain of sugar as part of its. Viruses free fulltext influenza virusmediated membrane. Influenza virus hemagglutinin and neuraminidase, but not the. A computational assay that explores the hemagglutininneuraminidase. Balanced hemagglutinin and neuraminidase activities are critical for efficient replication of influenza a virus. Hemagglutinin neuraminidase hn protein, which is responsible for virus attachment, interacts with the fusion protein in a virus typespecific manner to induce efficient membrane fusion. Influenza hemagglutinin and neuraminidase membrane. Role of the hemagglutininneuraminidase protein in the. Modification of the hemagglutinin cleavage site allows. The neuraminidase inhibitor drugs oseltamivir, zanamivir, peramivir, and laninamivir share a common mechanism of action. Neuraminidase is a viral enzyme that prevents the spread of influenza virus infection and it is found on the surface of the virus and is made up of 582 amino acids. All but h17n10 and h18n11 subtypes, found to date in peruvian bats,14, circulate in wild aquatic birds, which is by far the largest of the known natural iav reservoirs, which also include humans, swine, horses, dogs, and seals. Viruses that possess hes include influenza c virus, toroviruses, and coronaviruses. Influenza a virus hemagglutinin mutations associated with.
Role of the hemagglutininneuraminidase protein in the mechanism. Hemagglutinin and neuraminidase protrude from the outer surface of the influenza virus and neuraminidase is a constituent of the enveloping membrane that surrounds the viral contents. Additional methods information, including figures and tables pdf. Viral hemagglutinin is a homotrimeric receptor, and thus, tri or.
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