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Yoshihiro Kawaoka - One of the best experts on this subject based on the ideXlab platform.
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synergistic effect of the pdz and p85β binding domains of the ns1 protein on virulence of an Avian h5n1 influenza a Virus
Journal of Virology, 2013Co-Authors: Shufang Fan, Gabriele Neumann, Chairul A Nidom, Hualan Chen, Catherine A Macken, Makoto Ozawa, Hideo Goto, N F N Iswahyudi, Yoshihiro KawaokaAbstract:The influenza A Virus NS1 protein affects virulence through several mechanisms, including the host's innate immune response and various signaling pathways. Highly pathogenic Avian influenza (HPAI) Viruses of the H5N1 subtype continue to evolve through reassortment and mutations. Our recent phylogenetic analysis identified a group of HPAI H5N1 Viruses with two characteristic mutations in NS1: the Avian Virus-type PDZ domain-binding motif ESEV (which affects virulence) was replaced with ESKV, and NS1-138F (which is highly conserved among all influenza A Viruses and may affect the activation of the phosphatidylinositol 3-kinase [PI3K]/Akt signaling pathway) was replaced with NS1-138Y. Here, we show that an HPAI H5N1 Virus (A/duck/Hunan/69/2004) encoding NS1-ESKV and NS1-138Y was confined to the respiratory tract of infected mice, whereas a mutant encoding NS1-ESEV and NS1-138F caused systemic infection and killed mice more efficiently. Mutation of either one of these sites had small effects on virulence. In addition, we found that the amino acid at NS1-138 affected not only the induction of the PI3K/Akt pathway but also the interaction of NS1 with cellular PDZ domain proteins. Similarly, the mutation in the PDZ domain-binding motif of NS1 altered its binding to cellular PDZ domain proteins and affected Akt phosphorylation. These findings suggest a functional interplay between the mutations at NS1-138 and NS1-229 that results in a synergistic effect on influenza virulence.
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host range restriction and pathogenicity in the context of influenza pandemic
Emerging Infectious Diseases, 2006Co-Authors: Gabriele Neumann, Yoshihiro KawaokaAbstract:Influenza A Viruses cause pandemics at random intervals. Pandemics are caused by Viruses that contain a hemagglutinin (HA) surface glycoprotein to which human populations are immunologically naive. Such an HA can be introduced into the human population through reassortment between human and Avian Virus strains or through the direct transfer of an Avian influenza Virus to humans. The factors that determine the interspecies transmission and pathogenicity of influenza Viruses are still poorly understood; however, the HA protein plays an important role in overcoming the interspecies barrier and in virulence in Avian influenza Viruses. Recently, the RNA polymerase (PB2) protein has also been recognized as a critical factor in host range restriction, while the nonstructural (NS1) protein affects the initial host immune responses. We summarize current knowledge of viral factors that determine host range restriction and pathogenicity of influenza A Viruses.
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amino acids responsible for the absolute sialidase activity of the influenza a Virus neuraminidase relationship to growth in the duck intestine
Journal of Virology, 2001Co-Authors: Darwyn Kobasa, Yoshihiro Kawaoka, Krisna WellsAbstract:The 1957 human pandemic strain of influenza A Virus contained an Avian Virus hemagglutinin (HA) and neuraminidase (NA), both of which acquired specificity for the human receptor, N-acetylneuraminic acid linked to galactose of cellular glycoconjugates via an α2-6 bond (NeuAcα2-6Gal). Although the NA retained considerable specificity for NeuAcα2-3Gal, its original substrate in ducks, it lost the ability to support viral growth in the duck intestine, suggesting a growth-restrictive change other than a shift in substrate specificity. To test this possibility, we generated a panel of reassortant Viruses that expressed the NA genes of human H2N2 Viruses isolated from 1957 to 1968 with all other genes from the Avian Virus A/duck/Hong Kong/278/78 (H9N2). Only the NA of A/Singapore/1/57 supported efficient viral growth in the intestines of orally inoculated ducks. The growth-supporting capacity of the NA correlated with a high level of enzymatic activity, comparable to that found to be associated with Avian Virus NAs. The specific activities of the A/Ann Arbor/6/60 and A/England/12/62 NAs, which showed greatly restricted abilities to support viral growth in ducks, were only 8 and 5%, respectively, of the NA specific activity for A/Singapore/1/57. Using chimeric constructs based on A/Singapore/1/57 and A/England/12/62 NAs, we localized the determinants of high specific NA activity to a region containing six amino acid substitutions in A/England/12/62: Ser331→Arg, Asp339→Asn, Asn367→Ser, Ser370→Leu, Asn400→Ser, and Pro431→Glu. Five of these six residues (excluding Asn400) were required and sufficient for the full specific activity of the A/Singapore/1/57 NA. Thus, in addition to a change in substrate specificity, a reduction in high specific activity may be required for the adaptation of Avian Virus NAs to growth in humans. This change is likely needed to maintain an optimal balance between NA activity and the lower affinity shown by human Virus HAs for their cellular receptor.
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pandemic threat posed by Avian influenza a Viruses
Clinical Microbiology Reviews, 2001Co-Authors: Yoshihiro Kawaoka, Taisuke HorimotoAbstract:Influenza pandemics, defined as global outbreaks of the disease due to Viruses with new antigenic subtypes, have exacted high death tolls from human populations. The last two pandemics were caused by hybrid Viruses, or reassortants, that harbored a combination of Avian and human viral genes. Avian influenza Viruses are therefore key contributors to the emergence of human influenza pandemics. In 1997, an H5N1 influenza Virus was directly transmitted from birds in live poultry markets in Hong Kong to humans. Eighteen people were infected in this outbreak, six of whom died. This Avian Virus exhibited high virulence in both Avian and mammalian species, causing systemic infection in both chickens and mice. Subsequently, another Avian Virus with the H9N2 subtype was directly transmitted from birds to humans in Hong Kong. Interestingly, the genes encoding the internal proteins of the H9N2 Virus are genetically highly related to those of the H5N1 Virus, suggesting a unique property of these gene products. The identification of Avian Viruses in humans underscores the potential of these and similar strains to produce devastating influenza outbreaks in major population centers. Although highly pathogenic Avian influenza Viruses had been identified before the 1997 outbreak in Hong Kong, their devastating effects had been confined to poultry. With the Hong Kong outbreak, it became clear that the virulence potential of these Viruses extended to humans.
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early alterations of the receptor binding properties of h1 h2 and h3 Avian influenza Virus hemagglutinins after their introduction into mammals
Journal of Virology, 2000Co-Authors: Mikhail Matrosovich, Yoshihiro Kawaoka, Maria R Castrucci, Isabella Donatelli, Alexander B Tuzikov, N V Bovin, A S Gambaryan, Alexander KlimovAbstract:Interspecies transmission of influenza A Viruses circulating in wild aquatic birds occasionally results in influenza outbreaks in mammals, including humans. To identify early changes in the receptor binding properties of the Avian Virus hemagglutinin (HA) after interspecies transmission and to determine the amino acid substitutions responsible for these alterations, we studied the HAs of the initial isolates from the human pandemics of 1957 (H2N2) and 1968 (H3N2), the European swine epizootic of 1979 (H1N1), and the seal epizootic of 1992 (H3N3), all of which were caused by the introduction of Avian Virus HAs into these species. The Viruses were assayed for their ability to bind the synthetic sialylglycopolymers 3'SL-PAA and 6'SLN-PAA, which contained, respectively, 3'-sialyllactose (the receptor determinant preferentially recognized by Avian influenza Viruses) and 6'-sialyl(N-acetyllactosamine) (the receptor determinant for human Viruses). Avian and seal Viruses bound 6'SLN-PAA very weakly, whereas the earliest available human and swine epidemic Viruses bound this polymer with a higher affinity. For the H2 and H3 strains, a single mutation, 226Q-->L, increased binding to 6'SLN-PAA, while among H1 swine Viruses, the 190E-->D and 225G-->E mutations in the HA appeared important for the increased affinity of the Viruses for 6'SLN-PAA. Amino acid substitutions at positions 190 and 225 with respect to the Avian Virus consensus sequence are also present in H1 human Viruses, including those that circulated in 1918, suggesting that substitutions at these positions are important for the generation of H1 human pandemic strains. These results show that the receptor-binding specificity of the HA is altered early after the transmission of an Avian Virus to humans and pigs and, therefore, may be a prerequisite for the highly effective replication and spread which characterize epidemic strains.
Mikhail Matrosovich - One of the best experts on this subject based on the ideXlab platform.
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Functional significance of the hemadsorption activity of influenza Virus neuraminidase and its alteration in pandemic Viruses
Archives of Virology, 2009Co-Authors: Jennifer Uhlendorff, Tatyana Matrosovich, Hans-dieter Klenk, Mikhail MatrosovichAbstract:Human influenza Viruses derive their genes from Avian Viruses. The neuraminidase (NA) of the Avian Viruses has, in addition to the catalytic site, a separate sialic acid binding site (hemadsorption site) that is not present in human Viruses. The biological significance of the NA hemadsorption activity in Avian influenza Viruses remained elusive. A sequence database analysis revealed that the NAs of the majority of human H2N2 Viruses isolated during the influenza pandemic of 1957 differ from their putative Avian precursor by amino acid substitutions in the hemadsorption site. We found that the NA of a representative pandemic Virus A/Singapore/1/57 (H2N2) lacks hemadsorption activity and that a single reversion to the Avian-Virus-like sequence (N367S) restores hemadsorption. Using this hemadsorption-positive NA, we generated three NA variants with substitutions S370L, N400S and W403R that have been found in the hemadsorption site of human H2N2 Viruses. Each substitution abolished hemadsorption activity. Although, there was no correlation between hemadsorption activity of the NA variants and their enzymatic activity with respect to monovalent substrates, all four hemadsorption-negative NAs desialylated macromolecular substrates significantly slower than did the hemadsorption-positive counterpart. The NA of the 1918 pandemic Virus A/Brevig Mission/1/18 (H1N1) also differed from Avian N1 NAs by reduced hemadsorption activity and less efficient hydrolysis of macromolecular substrates. Our data indicate that the hemadsorption site serves to enhance the catalytic efficiency of NA and they suggest that, in addition to changes in the receptor-binding specificity of the hemagglutinin, alterations of the NA are needed for the emergence of pandemic influenza Viruses.
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human and Avian influenza Viruses target different cell types in cultures of human airway epithelium
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Mikhail Matrosovich, Tatyana Matrosovich, Thomas G Gray, Noel Allan Roberts, Hans-dieter KlenkAbstract:The recent human infections caused by H5N1, H9N2, and H7N7 Avian influenza Viruses highlighted the continuous threat of new pathogenic influenza Viruses emerging from a natural reservoir in birds. It is generally believed that replication of Avian influenza Viruses in humans is restricted by a poor fit of these Viruses to cellular receptors and extracellular inhibitors in the human respiratory tract. However, detailed mechanisms of this restriction remain obscure. Here, using cultures of differentiated human airway epithelial cells, we demonstrated that influenza Viruses enter the airway epithelium through specific target cells and that there were striking differences in this respect between human and Avian Viruses. During the course of a single-cycle infection, human Viruses preferentially infected nonciliated cells, whereas Avian Viruses as well as the egg-adapted human Virus variant with an Avian Virus-like receptor specificity mainly infected ciliated cells. This pattern correlated with the predominant localization of receptors for human Viruses (2-6-linked sialic acids) on nonciliated cells and of receptors for Avian Viruses (2-3-linked sialic acids) on ciliated cells. These findings suggest that although Avian influenza Viruses can infect human airway epithelium, their replication may be limited by a nonoptimal cellular tropism. Our data throw light on the mechanisms of generation of pandemic Viruses from their Avian progenitors and open avenues for cell level-oriented studies on the replication and pathogenicity of influenza Virus in humans.
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early alterations of the receptor binding properties of h1 h2 and h3 Avian influenza Virus hemagglutinins after their introduction into mammals
Journal of Virology, 2000Co-Authors: Mikhail Matrosovich, Yoshihiro Kawaoka, Maria R Castrucci, Isabella Donatelli, Alexander B Tuzikov, N V Bovin, A S Gambaryan, Alexander KlimovAbstract:Interspecies transmission of influenza A Viruses circulating in wild aquatic birds occasionally results in influenza outbreaks in mammals, including humans. To identify early changes in the receptor binding properties of the Avian Virus hemagglutinin (HA) after interspecies transmission and to determine the amino acid substitutions responsible for these alterations, we studied the HAs of the initial isolates from the human pandemics of 1957 (H2N2) and 1968 (H3N2), the European swine epizootic of 1979 (H1N1), and the seal epizootic of 1992 (H3N3), all of which were caused by the introduction of Avian Virus HAs into these species. The Viruses were assayed for their ability to bind the synthetic sialylglycopolymers 3'SL-PAA and 6'SLN-PAA, which contained, respectively, 3'-sialyllactose (the receptor determinant preferentially recognized by Avian influenza Viruses) and 6'-sialyl(N-acetyllactosamine) (the receptor determinant for human Viruses). Avian and seal Viruses bound 6'SLN-PAA very weakly, whereas the earliest available human and swine epidemic Viruses bound this polymer with a higher affinity. For the H2 and H3 strains, a single mutation, 226Q-->L, increased binding to 6'SLN-PAA, while among H1 swine Viruses, the 190E-->D and 225G-->E mutations in the HA appeared important for the increased affinity of the Viruses for 6'SLN-PAA. Amino acid substitutions at positions 190 and 225 with respect to the Avian Virus consensus sequence are also present in H1 human Viruses, including those that circulated in 1918, suggesting that substitutions at these positions are important for the generation of H1 human pandemic strains. These results show that the receptor-binding specificity of the HA is altered early after the transmission of an Avian Virus to humans and pigs and, therefore, may be a prerequisite for the highly effective replication and spread which characterize epidemic strains.
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early alterations of the receptor binding properties of h1 h2 and h3 Avian influenza Virus hemagglutinins after their introduction into mammals
Journal of Virology, 2000Co-Authors: Mikhail Matrosovich, Yoshihiro Kawaoka, Maria R Castrucci, Isabella Donatelli, Alexander B Tuzikov, N V Bovin, A S Gambaryan, Alexander KlimovAbstract:Wild aquatic birds are the natural reservoirs for influenza A Viruses of all known hemagglutinin (HA) and neuraminidase (NA) subtypes. Such Viruses are occasionally transmitted to other species, including domestic poultry, sea mammals, pigs, horses, and humans, where they can cause severe outbreaks of influenza (reviewed in reference 40). For example, the 1957 and 1968 influenza pandemics originated from Avian-human reassortant Viruses (H2N2 “Asian” pandemic Virus in 1957; H3N2 “Hong Kong” pandemic Virus in 1968). Recent introduction of an H1N1 Avian Virus into pigs led to the emergence of a so-called Avian-like swine Virus lineage (36). Although progenitors of H1N1 human Viruses and H1N1 “classical” swine Viruses have not been unambiguously identified, they too are thought to have originated from Avian Virus precursors. All influenza A Viruses bind to cellular glycoconjugates containing terminal sialic acid, but the exact molecules (glycoproteins or glycolipids) that serve as biological receptors of influenza Viruses in birds and other species remain to be determined. Cellular receptors of influenza Viruses appear to differ among distinct animal species because the binding specificity of Viruses varies considerably depending on the host animals from which the Viruses are isolated. Namely, human influenza A and B strains and swine influenza Viruses preferentially bind receptors that contain terminal 6′-sialyl(N-acetyllactosamine) residues (6′SLN; Neu5Acα2-6Galβ1-4GlcNAc), whereas Avian and equine Viruses bind poorly to 6′SLN, preferring instead the terminal 3′-sialylgalactose (Neu5Acα2-3Gal) moiety (8, 13, 23, 33; see also reference 28 for a review of earlier data). The molecular mechanisms by which influenza Viruses distinguish between these sialyloligosaccharide determinants are poorly defined. A comparison of the amino acid sequences of influenza A Viruses from different hosts revealed six amino acids in the HA receptor-binding site, which are highly conserved among Avian Viruses (138A, 190E, 194L, 225G, 226Q, and 228G), but bear substitutions in human Viruses (23). This finding suggested that mutations at these positions are required for adaptation of the Avian Virus HA to human hosts. However, the role of individual mutations at most of these positions in the alteration of the HA receptor-binding properties remains undefined. Both H2 and H3 human Viruses bear the same substitutions, 226Q→L and 228G→S, with respect to the Avian consensus sequence (8). The single mutation 226L→Q in the H3 human Virus HA changes its specificity from preferential Neu5Acα2-6Gal recognition to preferential Neu5Acα2-3Gal binding (31, 32). As was shown by site-directed mutagenesis, mutations at position 228 of the human H3 HA affect HA binding to erythrocytes (19, 39); however, the effects of such mutations on the ability of the HA to recognize the type of Neu5Ac-Gal linkage were not clearly determined. Interestingly, some H2N2 Viruses isolated from humans during the first year of the 1957 pandemic contain 228G (17) as do most Avian Viruses, whereas some Avian H3 Viruses contain “human” 228S (2, 16). The receptor-binding properties of such atypical Avian and human Viruses have not been characterized. Thus, the contribution of substitutions at position 228 to the adaptation of Avian Viruses to human receptors remains unknown. The currently circulating human H1N1 Viruses are thought to have originated from an Avian Virus that was transmitted to humans at the beginning of this century and gave rise to the so-called Spanish influenza pandemic. At least four mutations in the conserved positions of the Avian receptor-binding site (138, 190, 194, and 225) separate contemporary H1 human Viruses from Avian strains (23, 33), and those in positions 190 and 225 are also present in the recently sequenced H1N1 human Viruses from 1918 (30). Effects of substitutions at these positions on the HA receptor-binding properties and their possible contribution to the adaptation of the H1 Avian HA to human hosts are unclear. Previous studies compared the receptor-binding specificities of influenza Viruses that were already well adapted to their hosts, making it difficult to define minimal changes in the specificity of the Avian HA required for efficient replication in a new species. Furthermore, because many mutations have been introduced into the HA of these Viruses since transmission from birds, it has been difficult to determine the contribution of each mutation to the binding specificity of this protein. We compare here the receptor-binding properties of the earliest available influenza Viruses isolated during the 1957 and 1968 human pandemics and during swine and seal epizootics with those of closely related Avian Viruses of the H1, H2, and H3 subtypes. Two major questions were addressed: what are the earliest detectable alterations in the receptor-binding specificity of the Avian HA after introduction into a new host, and what are the most critical mutations in the HA that account for these changes?
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early alterations of the receptor binding properties of h1 h2 and h3 Avian influenza Virus hemagglutinins after their introduction into mammals
Journal of Virology, 2000Co-Authors: Mikhail Matrosovich, Yoshihiro Kawaoka, Maria R Castrucci, Isabella Donatelli, Alexander B Tuzikov, N V Bovin, A S Gambaryan, Alexander KlimovAbstract:Wild aquatic birds are the natural reservoirs for influenza A Viruses of all known hemagglutinin (HA) and neuraminidase (NA) subtypes. Such Viruses are occasionally transmitted to other species, including domestic poultry, sea mammals, pigs, horses, and humans, where they can cause severe outbreaks of influenza (reviewed in reference 40). For example, the 1957 and 1968 influenza pandemics originated from Avian-human reassortant Viruses (H2N2 “Asian” pandemic Virus in 1957; H3N2 “Hong Kong” pandemic Virus in 1968). Recent introduction of an H1N1 Avian Virus into pigs led to the emergence of a so-called Avian-like swine Virus lineage (36). Although progenitors of H1N1 human Viruses and H1N1 “classical” swine Viruses have not been unambiguously identified, they too are thought to have originated from Avian Virus precursors. All influenza A Viruses bind to cellular glycoconjugates containing terminal sialic acid, but the exact molecules (glycoproteins or glycolipids) that serve as biological receptors of influenza Viruses in birds and other species remain to be determined. Cellular receptors of influenza Viruses appear to differ among distinct animal species because the binding specificity of Viruses varies considerably depending on the host animals from which the Viruses are isolated. Namely, human influenza A and B strains and swine influenza Viruses preferentially bind receptors that contain terminal 6′-sialyl(N-acetyllactosamine) residues (6′SLN; Neu5Acα2-6Galβ1-4GlcNAc), whereas Avian and equine Viruses bind poorly to 6′SLN, preferring instead the terminal 3′-sialylgalactose (Neu5Acα2-3Gal) moiety (8, 13, 23, 33; see also reference 28 for a review of earlier data). The molecular mechanisms by which influenza Viruses distinguish between these sialyloligosaccharide determinants are poorly defined. A comparison of the amino acid sequences of influenza A Viruses from different hosts revealed six amino acids in the HA receptor-binding site, which are highly conserved among Avian Viruses (138A, 190E, 194L, 225G, 226Q, and 228G), but bear substitutions in human Viruses (23). This finding suggested that mutations at these positions are required for adaptation of the Avian Virus HA to human hosts. However, the role of individual mutations at most of these positions in the alteration of the HA receptor-binding properties remains undefined. Both H2 and H3 human Viruses bear the same substitutions, 226Q→L and 228G→S, with respect to the Avian consensus sequence (8). The single mutation 226L→Q in the H3 human Virus HA changes its specificity from preferential Neu5Acα2-6Gal recognition to preferential Neu5Acα2-3Gal binding (31, 32). As was shown by site-directed mutagenesis, mutations at position 228 of the human H3 HA affect HA binding to erythrocytes (19, 39); however, the effects of such mutations on the ability of the HA to recognize the type of Neu5Ac-Gal linkage were not clearly determined. Interestingly, some H2N2 Viruses isolated from humans during the first year of the 1957 pandemic contain 228G (17) as do most Avian Viruses, whereas some Avian H3 Viruses contain “human” 228S (2, 16). The receptor-binding properties of such atypical Avian and human Viruses have not been characterized. Thus, the contribution of substitutions at position 228 to the adaptation of Avian Viruses to human receptors remains unknown. The currently circulating human H1N1 Viruses are thought to have originated from an Avian Virus that was transmitted to humans at the beginning of this century and gave rise to the so-called Spanish influenza pandemic. At least four mutations in the conserved positions of the Avian receptor-binding site (138, 190, 194, and 225) separate contemporary H1 human Viruses from Avian strains (23, 33), and those in positions 190 and 225 are also present in the recently sequenced H1N1 human Viruses from 1918 (30). Effects of substitutions at these positions on the HA receptor-binding properties and their possible contribution to the adaptation of the H1 Avian HA to human hosts are unclear. Previous studies compared the receptor-binding specificities of influenza Viruses that were already well adapted to their hosts, making it difficult to define minimal changes in the specificity of the Avian HA required for efficient replication in a new species. Furthermore, because many mutations have been introduced into the HA of these Viruses since transmission from birds, it has been difficult to determine the contribution of each mutation to the binding specificity of this protein. We compare here the receptor-binding properties of the earliest available influenza Viruses isolated during the 1957 and 1968 human pandemics and during swine and seal epizootics with those of closely related Avian Viruses of the H1, H2, and H3 subtypes. Two major questions were addressed: what are the earliest detectable alterations in the receptor-binding specificity of the Avian HA after introduction into a new host, and what are the most critical mutations in the HA that account for these changes?
Isabella Donatelli - One of the best experts on this subject based on the ideXlab platform.
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early alterations of the receptor binding properties of h1 h2 and h3 Avian influenza Virus hemagglutinins after their introduction into mammals
Journal of Virology, 2000Co-Authors: Mikhail Matrosovich, Yoshihiro Kawaoka, Maria R Castrucci, Isabella Donatelli, Alexander B Tuzikov, N V Bovin, A S Gambaryan, Alexander KlimovAbstract:Interspecies transmission of influenza A Viruses circulating in wild aquatic birds occasionally results in influenza outbreaks in mammals, including humans. To identify early changes in the receptor binding properties of the Avian Virus hemagglutinin (HA) after interspecies transmission and to determine the amino acid substitutions responsible for these alterations, we studied the HAs of the initial isolates from the human pandemics of 1957 (H2N2) and 1968 (H3N2), the European swine epizootic of 1979 (H1N1), and the seal epizootic of 1992 (H3N3), all of which were caused by the introduction of Avian Virus HAs into these species. The Viruses were assayed for their ability to bind the synthetic sialylglycopolymers 3'SL-PAA and 6'SLN-PAA, which contained, respectively, 3'-sialyllactose (the receptor determinant preferentially recognized by Avian influenza Viruses) and 6'-sialyl(N-acetyllactosamine) (the receptor determinant for human Viruses). Avian and seal Viruses bound 6'SLN-PAA very weakly, whereas the earliest available human and swine epidemic Viruses bound this polymer with a higher affinity. For the H2 and H3 strains, a single mutation, 226Q-->L, increased binding to 6'SLN-PAA, while among H1 swine Viruses, the 190E-->D and 225G-->E mutations in the HA appeared important for the increased affinity of the Viruses for 6'SLN-PAA. Amino acid substitutions at positions 190 and 225 with respect to the Avian Virus consensus sequence are also present in H1 human Viruses, including those that circulated in 1918, suggesting that substitutions at these positions are important for the generation of H1 human pandemic strains. These results show that the receptor-binding specificity of the HA is altered early after the transmission of an Avian Virus to humans and pigs and, therefore, may be a prerequisite for the highly effective replication and spread which characterize epidemic strains.
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early alterations of the receptor binding properties of h1 h2 and h3 Avian influenza Virus hemagglutinins after their introduction into mammals
Journal of Virology, 2000Co-Authors: Mikhail Matrosovich, Yoshihiro Kawaoka, Maria R Castrucci, Isabella Donatelli, Alexander B Tuzikov, N V Bovin, A S Gambaryan, Alexander KlimovAbstract:Wild aquatic birds are the natural reservoirs for influenza A Viruses of all known hemagglutinin (HA) and neuraminidase (NA) subtypes. Such Viruses are occasionally transmitted to other species, including domestic poultry, sea mammals, pigs, horses, and humans, where they can cause severe outbreaks of influenza (reviewed in reference 40). For example, the 1957 and 1968 influenza pandemics originated from Avian-human reassortant Viruses (H2N2 “Asian” pandemic Virus in 1957; H3N2 “Hong Kong” pandemic Virus in 1968). Recent introduction of an H1N1 Avian Virus into pigs led to the emergence of a so-called Avian-like swine Virus lineage (36). Although progenitors of H1N1 human Viruses and H1N1 “classical” swine Viruses have not been unambiguously identified, they too are thought to have originated from Avian Virus precursors. All influenza A Viruses bind to cellular glycoconjugates containing terminal sialic acid, but the exact molecules (glycoproteins or glycolipids) that serve as biological receptors of influenza Viruses in birds and other species remain to be determined. Cellular receptors of influenza Viruses appear to differ among distinct animal species because the binding specificity of Viruses varies considerably depending on the host animals from which the Viruses are isolated. Namely, human influenza A and B strains and swine influenza Viruses preferentially bind receptors that contain terminal 6′-sialyl(N-acetyllactosamine) residues (6′SLN; Neu5Acα2-6Galβ1-4GlcNAc), whereas Avian and equine Viruses bind poorly to 6′SLN, preferring instead the terminal 3′-sialylgalactose (Neu5Acα2-3Gal) moiety (8, 13, 23, 33; see also reference 28 for a review of earlier data). The molecular mechanisms by which influenza Viruses distinguish between these sialyloligosaccharide determinants are poorly defined. A comparison of the amino acid sequences of influenza A Viruses from different hosts revealed six amino acids in the HA receptor-binding site, which are highly conserved among Avian Viruses (138A, 190E, 194L, 225G, 226Q, and 228G), but bear substitutions in human Viruses (23). This finding suggested that mutations at these positions are required for adaptation of the Avian Virus HA to human hosts. However, the role of individual mutations at most of these positions in the alteration of the HA receptor-binding properties remains undefined. Both H2 and H3 human Viruses bear the same substitutions, 226Q→L and 228G→S, with respect to the Avian consensus sequence (8). The single mutation 226L→Q in the H3 human Virus HA changes its specificity from preferential Neu5Acα2-6Gal recognition to preferential Neu5Acα2-3Gal binding (31, 32). As was shown by site-directed mutagenesis, mutations at position 228 of the human H3 HA affect HA binding to erythrocytes (19, 39); however, the effects of such mutations on the ability of the HA to recognize the type of Neu5Ac-Gal linkage were not clearly determined. Interestingly, some H2N2 Viruses isolated from humans during the first year of the 1957 pandemic contain 228G (17) as do most Avian Viruses, whereas some Avian H3 Viruses contain “human” 228S (2, 16). The receptor-binding properties of such atypical Avian and human Viruses have not been characterized. Thus, the contribution of substitutions at position 228 to the adaptation of Avian Viruses to human receptors remains unknown. The currently circulating human H1N1 Viruses are thought to have originated from an Avian Virus that was transmitted to humans at the beginning of this century and gave rise to the so-called Spanish influenza pandemic. At least four mutations in the conserved positions of the Avian receptor-binding site (138, 190, 194, and 225) separate contemporary H1 human Viruses from Avian strains (23, 33), and those in positions 190 and 225 are also present in the recently sequenced H1N1 human Viruses from 1918 (30). Effects of substitutions at these positions on the HA receptor-binding properties and their possible contribution to the adaptation of the H1 Avian HA to human hosts are unclear. Previous studies compared the receptor-binding specificities of influenza Viruses that were already well adapted to their hosts, making it difficult to define minimal changes in the specificity of the Avian HA required for efficient replication in a new species. Furthermore, because many mutations have been introduced into the HA of these Viruses since transmission from birds, it has been difficult to determine the contribution of each mutation to the binding specificity of this protein. We compare here the receptor-binding properties of the earliest available influenza Viruses isolated during the 1957 and 1968 human pandemics and during swine and seal epizootics with those of closely related Avian Viruses of the H1, H2, and H3 subtypes. Two major questions were addressed: what are the earliest detectable alterations in the receptor-binding specificity of the Avian HA after introduction into a new host, and what are the most critical mutations in the HA that account for these changes?
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early alterations of the receptor binding properties of h1 h2 and h3 Avian influenza Virus hemagglutinins after their introduction into mammals
Journal of Virology, 2000Co-Authors: Mikhail Matrosovich, Yoshihiro Kawaoka, Maria R Castrucci, Isabella Donatelli, Alexander B Tuzikov, N V Bovin, A S Gambaryan, Alexander KlimovAbstract:Wild aquatic birds are the natural reservoirs for influenza A Viruses of all known hemagglutinin (HA) and neuraminidase (NA) subtypes. Such Viruses are occasionally transmitted to other species, including domestic poultry, sea mammals, pigs, horses, and humans, where they can cause severe outbreaks of influenza (reviewed in reference 40). For example, the 1957 and 1968 influenza pandemics originated from Avian-human reassortant Viruses (H2N2 “Asian” pandemic Virus in 1957; H3N2 “Hong Kong” pandemic Virus in 1968). Recent introduction of an H1N1 Avian Virus into pigs led to the emergence of a so-called Avian-like swine Virus lineage (36). Although progenitors of H1N1 human Viruses and H1N1 “classical” swine Viruses have not been unambiguously identified, they too are thought to have originated from Avian Virus precursors. All influenza A Viruses bind to cellular glycoconjugates containing terminal sialic acid, but the exact molecules (glycoproteins or glycolipids) that serve as biological receptors of influenza Viruses in birds and other species remain to be determined. Cellular receptors of influenza Viruses appear to differ among distinct animal species because the binding specificity of Viruses varies considerably depending on the host animals from which the Viruses are isolated. Namely, human influenza A and B strains and swine influenza Viruses preferentially bind receptors that contain terminal 6′-sialyl(N-acetyllactosamine) residues (6′SLN; Neu5Acα2-6Galβ1-4GlcNAc), whereas Avian and equine Viruses bind poorly to 6′SLN, preferring instead the terminal 3′-sialylgalactose (Neu5Acα2-3Gal) moiety (8, 13, 23, 33; see also reference 28 for a review of earlier data). The molecular mechanisms by which influenza Viruses distinguish between these sialyloligosaccharide determinants are poorly defined. A comparison of the amino acid sequences of influenza A Viruses from different hosts revealed six amino acids in the HA receptor-binding site, which are highly conserved among Avian Viruses (138A, 190E, 194L, 225G, 226Q, and 228G), but bear substitutions in human Viruses (23). This finding suggested that mutations at these positions are required for adaptation of the Avian Virus HA to human hosts. However, the role of individual mutations at most of these positions in the alteration of the HA receptor-binding properties remains undefined. Both H2 and H3 human Viruses bear the same substitutions, 226Q→L and 228G→S, with respect to the Avian consensus sequence (8). The single mutation 226L→Q in the H3 human Virus HA changes its specificity from preferential Neu5Acα2-6Gal recognition to preferential Neu5Acα2-3Gal binding (31, 32). As was shown by site-directed mutagenesis, mutations at position 228 of the human H3 HA affect HA binding to erythrocytes (19, 39); however, the effects of such mutations on the ability of the HA to recognize the type of Neu5Ac-Gal linkage were not clearly determined. Interestingly, some H2N2 Viruses isolated from humans during the first year of the 1957 pandemic contain 228G (17) as do most Avian Viruses, whereas some Avian H3 Viruses contain “human” 228S (2, 16). The receptor-binding properties of such atypical Avian and human Viruses have not been characterized. Thus, the contribution of substitutions at position 228 to the adaptation of Avian Viruses to human receptors remains unknown. The currently circulating human H1N1 Viruses are thought to have originated from an Avian Virus that was transmitted to humans at the beginning of this century and gave rise to the so-called Spanish influenza pandemic. At least four mutations in the conserved positions of the Avian receptor-binding site (138, 190, 194, and 225) separate contemporary H1 human Viruses from Avian strains (23, 33), and those in positions 190 and 225 are also present in the recently sequenced H1N1 human Viruses from 1918 (30). Effects of substitutions at these positions on the HA receptor-binding properties and their possible contribution to the adaptation of the H1 Avian HA to human hosts are unclear. Previous studies compared the receptor-binding specificities of influenza Viruses that were already well adapted to their hosts, making it difficult to define minimal changes in the specificity of the Avian HA required for efficient replication in a new species. Furthermore, because many mutations have been introduced into the HA of these Viruses since transmission from birds, it has been difficult to determine the contribution of each mutation to the binding specificity of this protein. We compare here the receptor-binding properties of the earliest available influenza Viruses isolated during the 1957 and 1968 human pandemics and during swine and seal epizootics with those of closely related Avian Viruses of the H1, H2, and H3 subtypes. Two major questions were addressed: what are the earliest detectable alterations in the receptor-binding specificity of the Avian HA after introduction into a new host, and what are the most critical mutations in the HA that account for these changes?
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molecular basis for the generation in pigs of influenza a Viruses with pandemic potential
Journal of Virology, 1998Co-Authors: Toshihiro Ito, Nelson J S S Couceiro, Sorge Kelm, Linda G Baum, Scott Krauss, Maria R Castrucci, Isabella Donatelli, Hiroshi Kida, James C Paulson, Robert G WebsterAbstract:Genetic and biologic observations suggest that pigs may serve as “mixing vessels” for the generation of human-Avian influenza A Virus reassortants, similar to those responsible for the 1957 and 1968 pandemics. Here we demonstrate a structural basis for this hypothesis. Cell surface receptors for both human and Avian influenza Viruses were identified in the pig trachea, providing a milieu conducive to viral replication and genetic reassortment. Surprisingly, with continued replication, some Avian-like swine Viruses acquired the ability to recognize human Virus receptors, raising the possibility of their direct transmission to human populations. These findings help to explain the emergence of pandemic influenza Viruses and support the need for continued surveillance of swine for Viruses carrying Avian Virus genes.
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evolution of influenza a Virus nucleoprotein genes implications for the origins of h1n1 human and classical swine Viruses
Journal of Virology, 1991Co-Authors: Owen T Gorman, Yoshihiro Kawaoka, Isabella Donatelli, W J Bean, Yuanji Guo, R G WebsterAbstract:A phylogenetic analysis of 52 published and 37 new nucleoprotein (NP) gene sequences addressed the evolution and origin of human and swine influenza A Viruses. H1N1 human and classical swine Viruses (i.e., those related to Swine/Iowa/15/30) share a single common ancestor, which was estimated to have occurred in 1912 to 1913. From this common ancestor, human and classical swine Virus NP genes have evolved at similar rates that are higher than in Avian Virus NP genes (3.31 to 3.41 versus 1.90 nucleotide changes per year). At the protein level, human Virus NPs have evolved twice as fast as classical swine Virus NPs (0.66 versus 0.34 amino acid change per year). Despite evidence of frequent interspecies transmission of human and classical swine Viruses, our analysis indicates that these Viruses have evolved independently since well before the first isolates in the early 1930s. Although our analysis cannot reveal the original host, the ancestor Virus was Avianlike, showing only five amino acid differences from the root of the Avian Virus NP lineage. The common pattern of relationship and origin for the NP and other genes of H1N1 human and classical swine Viruses suggests that the common ancestor was an Avian Virus and not a reassortant derived from previous human or swine influenza A Viruses. The new Avianlike H1N1 swine Viruses in Europe may provide a model for the evolution of newly introduced Avian Viruses into the swine host reservoir. The NPs of these Viruses are evolving more rapidly than those of human or classical swine Viruses (4.50 nucleotide changes and 0.74 amino acid change per year), and when these rates are applied to pre-1930s human and classical swine Virus NPs, the predicted date of a common ancestor is 1918 rather than 1912 to 1913. Thus, our NP phylogeny is consistent with historical records and the proposal that a short time before 1918, a new H1N1 Avianlike Virus entered human or swine hosts (O. T. Gorman, R. O. Donis, Y. Kawaoka, and R. G. Webster, J. Virol. 64:4893-4902, 1990). This Virus provided the ancestors of all known human influenza A Virus genes, except for HA, NA, and PB1, which have since been reassorted from Avian Viruses. We propose that during 1918 a virulent strain of this new Avianlike Virus caused a severe human influenza pandemic and that the pandemic Virus was introduced into North American swine populations, constituting the origin of classical swine Virus.
Maria R Castrucci - One of the best experts on this subject based on the ideXlab platform.
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early alterations of the receptor binding properties of h1 h2 and h3 Avian influenza Virus hemagglutinins after their introduction into mammals
Journal of Virology, 2000Co-Authors: Mikhail Matrosovich, Yoshihiro Kawaoka, Maria R Castrucci, Isabella Donatelli, Alexander B Tuzikov, N V Bovin, A S Gambaryan, Alexander KlimovAbstract:Wild aquatic birds are the natural reservoirs for influenza A Viruses of all known hemagglutinin (HA) and neuraminidase (NA) subtypes. Such Viruses are occasionally transmitted to other species, including domestic poultry, sea mammals, pigs, horses, and humans, where they can cause severe outbreaks of influenza (reviewed in reference 40). For example, the 1957 and 1968 influenza pandemics originated from Avian-human reassortant Viruses (H2N2 “Asian” pandemic Virus in 1957; H3N2 “Hong Kong” pandemic Virus in 1968). Recent introduction of an H1N1 Avian Virus into pigs led to the emergence of a so-called Avian-like swine Virus lineage (36). Although progenitors of H1N1 human Viruses and H1N1 “classical” swine Viruses have not been unambiguously identified, they too are thought to have originated from Avian Virus precursors. All influenza A Viruses bind to cellular glycoconjugates containing terminal sialic acid, but the exact molecules (glycoproteins or glycolipids) that serve as biological receptors of influenza Viruses in birds and other species remain to be determined. Cellular receptors of influenza Viruses appear to differ among distinct animal species because the binding specificity of Viruses varies considerably depending on the host animals from which the Viruses are isolated. Namely, human influenza A and B strains and swine influenza Viruses preferentially bind receptors that contain terminal 6′-sialyl(N-acetyllactosamine) residues (6′SLN; Neu5Acα2-6Galβ1-4GlcNAc), whereas Avian and equine Viruses bind poorly to 6′SLN, preferring instead the terminal 3′-sialylgalactose (Neu5Acα2-3Gal) moiety (8, 13, 23, 33; see also reference 28 for a review of earlier data). The molecular mechanisms by which influenza Viruses distinguish between these sialyloligosaccharide determinants are poorly defined. A comparison of the amino acid sequences of influenza A Viruses from different hosts revealed six amino acids in the HA receptor-binding site, which are highly conserved among Avian Viruses (138A, 190E, 194L, 225G, 226Q, and 228G), but bear substitutions in human Viruses (23). This finding suggested that mutations at these positions are required for adaptation of the Avian Virus HA to human hosts. However, the role of individual mutations at most of these positions in the alteration of the HA receptor-binding properties remains undefined. Both H2 and H3 human Viruses bear the same substitutions, 226Q→L and 228G→S, with respect to the Avian consensus sequence (8). The single mutation 226L→Q in the H3 human Virus HA changes its specificity from preferential Neu5Acα2-6Gal recognition to preferential Neu5Acα2-3Gal binding (31, 32). As was shown by site-directed mutagenesis, mutations at position 228 of the human H3 HA affect HA binding to erythrocytes (19, 39); however, the effects of such mutations on the ability of the HA to recognize the type of Neu5Ac-Gal linkage were not clearly determined. Interestingly, some H2N2 Viruses isolated from humans during the first year of the 1957 pandemic contain 228G (17) as do most Avian Viruses, whereas some Avian H3 Viruses contain “human” 228S (2, 16). The receptor-binding properties of such atypical Avian and human Viruses have not been characterized. Thus, the contribution of substitutions at position 228 to the adaptation of Avian Viruses to human receptors remains unknown. The currently circulating human H1N1 Viruses are thought to have originated from an Avian Virus that was transmitted to humans at the beginning of this century and gave rise to the so-called Spanish influenza pandemic. At least four mutations in the conserved positions of the Avian receptor-binding site (138, 190, 194, and 225) separate contemporary H1 human Viruses from Avian strains (23, 33), and those in positions 190 and 225 are also present in the recently sequenced H1N1 human Viruses from 1918 (30). Effects of substitutions at these positions on the HA receptor-binding properties and their possible contribution to the adaptation of the H1 Avian HA to human hosts are unclear. Previous studies compared the receptor-binding specificities of influenza Viruses that were already well adapted to their hosts, making it difficult to define minimal changes in the specificity of the Avian HA required for efficient replication in a new species. Furthermore, because many mutations have been introduced into the HA of these Viruses since transmission from birds, it has been difficult to determine the contribution of each mutation to the binding specificity of this protein. We compare here the receptor-binding properties of the earliest available influenza Viruses isolated during the 1957 and 1968 human pandemics and during swine and seal epizootics with those of closely related Avian Viruses of the H1, H2, and H3 subtypes. Two major questions were addressed: what are the earliest detectable alterations in the receptor-binding specificity of the Avian HA after introduction into a new host, and what are the most critical mutations in the HA that account for these changes?
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early alterations of the receptor binding properties of h1 h2 and h3 Avian influenza Virus hemagglutinins after their introduction into mammals
Journal of Virology, 2000Co-Authors: Mikhail Matrosovich, Yoshihiro Kawaoka, Maria R Castrucci, Isabella Donatelli, Alexander B Tuzikov, N V Bovin, A S Gambaryan, Alexander KlimovAbstract:Interspecies transmission of influenza A Viruses circulating in wild aquatic birds occasionally results in influenza outbreaks in mammals, including humans. To identify early changes in the receptor binding properties of the Avian Virus hemagglutinin (HA) after interspecies transmission and to determine the amino acid substitutions responsible for these alterations, we studied the HAs of the initial isolates from the human pandemics of 1957 (H2N2) and 1968 (H3N2), the European swine epizootic of 1979 (H1N1), and the seal epizootic of 1992 (H3N3), all of which were caused by the introduction of Avian Virus HAs into these species. The Viruses were assayed for their ability to bind the synthetic sialylglycopolymers 3'SL-PAA and 6'SLN-PAA, which contained, respectively, 3'-sialyllactose (the receptor determinant preferentially recognized by Avian influenza Viruses) and 6'-sialyl(N-acetyllactosamine) (the receptor determinant for human Viruses). Avian and seal Viruses bound 6'SLN-PAA very weakly, whereas the earliest available human and swine epidemic Viruses bound this polymer with a higher affinity. For the H2 and H3 strains, a single mutation, 226Q-->L, increased binding to 6'SLN-PAA, while among H1 swine Viruses, the 190E-->D and 225G-->E mutations in the HA appeared important for the increased affinity of the Viruses for 6'SLN-PAA. Amino acid substitutions at positions 190 and 225 with respect to the Avian Virus consensus sequence are also present in H1 human Viruses, including those that circulated in 1918, suggesting that substitutions at these positions are important for the generation of H1 human pandemic strains. These results show that the receptor-binding specificity of the HA is altered early after the transmission of an Avian Virus to humans and pigs and, therefore, may be a prerequisite for the highly effective replication and spread which characterize epidemic strains.
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early alterations of the receptor binding properties of h1 h2 and h3 Avian influenza Virus hemagglutinins after their introduction into mammals
Journal of Virology, 2000Co-Authors: Mikhail Matrosovich, Yoshihiro Kawaoka, Maria R Castrucci, Isabella Donatelli, Alexander B Tuzikov, N V Bovin, A S Gambaryan, Alexander KlimovAbstract:Wild aquatic birds are the natural reservoirs for influenza A Viruses of all known hemagglutinin (HA) and neuraminidase (NA) subtypes. Such Viruses are occasionally transmitted to other species, including domestic poultry, sea mammals, pigs, horses, and humans, where they can cause severe outbreaks of influenza (reviewed in reference 40). For example, the 1957 and 1968 influenza pandemics originated from Avian-human reassortant Viruses (H2N2 “Asian” pandemic Virus in 1957; H3N2 “Hong Kong” pandemic Virus in 1968). Recent introduction of an H1N1 Avian Virus into pigs led to the emergence of a so-called Avian-like swine Virus lineage (36). Although progenitors of H1N1 human Viruses and H1N1 “classical” swine Viruses have not been unambiguously identified, they too are thought to have originated from Avian Virus precursors. All influenza A Viruses bind to cellular glycoconjugates containing terminal sialic acid, but the exact molecules (glycoproteins or glycolipids) that serve as biological receptors of influenza Viruses in birds and other species remain to be determined. Cellular receptors of influenza Viruses appear to differ among distinct animal species because the binding specificity of Viruses varies considerably depending on the host animals from which the Viruses are isolated. Namely, human influenza A and B strains and swine influenza Viruses preferentially bind receptors that contain terminal 6′-sialyl(N-acetyllactosamine) residues (6′SLN; Neu5Acα2-6Galβ1-4GlcNAc), whereas Avian and equine Viruses bind poorly to 6′SLN, preferring instead the terminal 3′-sialylgalactose (Neu5Acα2-3Gal) moiety (8, 13, 23, 33; see also reference 28 for a review of earlier data). The molecular mechanisms by which influenza Viruses distinguish between these sialyloligosaccharide determinants are poorly defined. A comparison of the amino acid sequences of influenza A Viruses from different hosts revealed six amino acids in the HA receptor-binding site, which are highly conserved among Avian Viruses (138A, 190E, 194L, 225G, 226Q, and 228G), but bear substitutions in human Viruses (23). This finding suggested that mutations at these positions are required for adaptation of the Avian Virus HA to human hosts. However, the role of individual mutations at most of these positions in the alteration of the HA receptor-binding properties remains undefined. Both H2 and H3 human Viruses bear the same substitutions, 226Q→L and 228G→S, with respect to the Avian consensus sequence (8). The single mutation 226L→Q in the H3 human Virus HA changes its specificity from preferential Neu5Acα2-6Gal recognition to preferential Neu5Acα2-3Gal binding (31, 32). As was shown by site-directed mutagenesis, mutations at position 228 of the human H3 HA affect HA binding to erythrocytes (19, 39); however, the effects of such mutations on the ability of the HA to recognize the type of Neu5Ac-Gal linkage were not clearly determined. Interestingly, some H2N2 Viruses isolated from humans during the first year of the 1957 pandemic contain 228G (17) as do most Avian Viruses, whereas some Avian H3 Viruses contain “human” 228S (2, 16). The receptor-binding properties of such atypical Avian and human Viruses have not been characterized. Thus, the contribution of substitutions at position 228 to the adaptation of Avian Viruses to human receptors remains unknown. The currently circulating human H1N1 Viruses are thought to have originated from an Avian Virus that was transmitted to humans at the beginning of this century and gave rise to the so-called Spanish influenza pandemic. At least four mutations in the conserved positions of the Avian receptor-binding site (138, 190, 194, and 225) separate contemporary H1 human Viruses from Avian strains (23, 33), and those in positions 190 and 225 are also present in the recently sequenced H1N1 human Viruses from 1918 (30). Effects of substitutions at these positions on the HA receptor-binding properties and their possible contribution to the adaptation of the H1 Avian HA to human hosts are unclear. Previous studies compared the receptor-binding specificities of influenza Viruses that were already well adapted to their hosts, making it difficult to define minimal changes in the specificity of the Avian HA required for efficient replication in a new species. Furthermore, because many mutations have been introduced into the HA of these Viruses since transmission from birds, it has been difficult to determine the contribution of each mutation to the binding specificity of this protein. We compare here the receptor-binding properties of the earliest available influenza Viruses isolated during the 1957 and 1968 human pandemics and during swine and seal epizootics with those of closely related Avian Viruses of the H1, H2, and H3 subtypes. Two major questions were addressed: what are the earliest detectable alterations in the receptor-binding specificity of the Avian HA after introduction into a new host, and what are the most critical mutations in the HA that account for these changes?
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molecular basis for the generation in pigs of influenza a Viruses with pandemic potential
Journal of Virology, 1998Co-Authors: Toshihiro Ito, Nelson J S S Couceiro, Sorge Kelm, Linda G Baum, Scott Krauss, Maria R Castrucci, Isabella Donatelli, Hiroshi Kida, James C Paulson, Robert G WebsterAbstract:Genetic and biologic observations suggest that pigs may serve as “mixing vessels” for the generation of human-Avian influenza A Virus reassortants, similar to those responsible for the 1957 and 1968 pandemics. Here we demonstrate a structural basis for this hypothesis. Cell surface receptors for both human and Avian influenza Viruses were identified in the pig trachea, providing a milieu conducive to viral replication and genetic reassortment. Surprisingly, with continued replication, some Avian-like swine Viruses acquired the ability to recognize human Virus receptors, raising the possibility of their direct transmission to human populations. These findings help to explain the emergence of pandemic influenza Viruses and support the need for continued surveillance of swine for Viruses carrying Avian Virus genes.
John J. Skehel - One of the best experts on this subject based on the ideXlab platform.
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evolution of the receptor binding properties of the influenza a h3n2 hemagglutinin
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Y P Lin, X Xiong, Stephen A Wharton, Stephen R Martin, P J Coombs, Sebastien G Vachieri, Evangelos Christodoulou, Philip A Walker, J Liu, John J. SkehelAbstract:The hemagglutinin (HA) of influenza A(H3N2) Virus responsible for the 1968 influenza pandemic derived from an Avian Virus. On introduction into humans, its receptor binding properties had changed from a preference for Avian receptors (α2,3-linked sialic acid) to a preference for human receptors (α2,6-linked sialic acid). By 2001, the avidity of human H3 Viruses for Avian receptors had declined, and since then the affinity for human receptors has also decreased significantly. These changes in receptor binding, which correlate with increased difficulties in Virus propagation in vitro and in antigenic analysis, have been assessed by Virus hemagglutination of erythrocytes from different species and quantified by measuring Virus binding to receptor analogs using surface biolayer interferometry. Crystal structures of HA–receptor analog complexes formed with HAs from Viruses isolated in 2004 and 2005 reveal significant differences in the conformation of the 220-loop of HA1, relative to the 1968 structure, resulting in altered interactions between the HA and the receptor analog that explain the changes in receptor affinity. Site-specific mutagenesis shows the HA1 Asp-225→Asn substitution to be the key determinant of the decreased receptor binding in Viruses circulating since 2005. Our results indicate that the evolution of human influenza A(H3N2) Viruses since 1968 has produced a Virus with a low propensity to bind human receptor analogs, and this loss of avidity correlates with the marked reduction in A(H3N2) Virus disease impact in the last 10 y.
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The structure of H5N1 Avian influenza neuraminidase suggests new opportunities for drug design
Nature, 2006Co-Authors: Rupert J. Russell, Lesley F. Haire, D.j. Stevens, Patrick J. Collins, Yi Pu Lin, G. Michael Blackburn, Alan Hay, Steven J. Gamblin, John J. SkehelAbstract:The worldwide spread of H5N1 Avian influenza has raised concerns that this Virus might acquire the ability to pass readily among humans and cause a pandemic. Two anti-influenza drugs currently being used to treat infected patients are oseltamivir (Tamiflu) and zanamivir (Relenza), both of which target the neuraminidase enzyme of the Virus. Reports of the emergence of drug resistance make the development of new anti-influenza molecules a priority. Neuraminidases from influenza type A Viruses form two genetically distinct groups: group-1 contains the N1 neuraminidase of the H5N1 Avian Virus and group-2 contains the N2 and N9 enzymes used for the structure-based design of current drugs. Here we show by X-ray crystallography that these two groups are structurally distinct. Group-1 neuraminidases contain a cavity adjacent to their active sites that closes on ligand binding. Our analysis suggests that it may be possible to exploit the size and location of the group-1 cavity to develop new anti-influenza drugs.
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h5 Avian and h9 swine influenza Virus haemagglutinin structures possible origin of influenza subtypes
The EMBO Journal, 2002Co-Authors: D.j. Stevens, John J. Skehel, Don C WileyAbstract:There are 15 subtypes of influenza A Virus (H1–H15), all of which are found in Avian species. Three caused pandemics in the last century: H1 in 1918 (and 1977), H2 in 1957 and H3 in 1968. In 1997, an H5 Avian Virus and in 1999 an H9 Virus caused outbreaks of respiratory disease in Hong Kong. We have determined the three-dimensional structures of the haemagglutinins (HAs) from H5 Avian and H9 swine Viruses closely related to the Viruses isolated from humans in Hong Kong. We have compared them with known structures of the H3 HA from the Virus that caused the 1968 H3 pandemic and of the HA–esterase–fusion (HEF) glycoprotein from an influenza C Virus. Structure and sequence comparisons suggest that HA subtypes may have originated by diversification of properties that affected the metastability of HAs required for their membrane fusion activities in viral infection.
