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  • 1
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    Online Resource
    Plasticity of Amino Acid Residue 145 Near the Receptor Binding Site of H3 Swine Influenza A Viruses and Its Impact on Receptor Binding and Antibody Recognition
    American Society for Microbiology ; 2019
    In:  Journal of Virology Vol. 93, No. 2 ( 2019-01-15)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 93, No. 2 ( 2019-01-15)
    Abstract: The hemagglutinin (HA), a glycoprotein on the surface of influenza A virus (IAV), initiates the virus life cycle by binding to terminal sialic acid (SA) residues on host cells. The HA gradually accumulates amino acid substitutions that allow IAV to escape immunity through a mechanism known as antigenic drift. We recently confirmed that a small set of amino acid residues are largely responsible for driving antigenic drift in swine-origin H3 IAV. All identified residues are located adjacent to the HA receptor binding site (RBS), suggesting that substitutions associated with antigenic drift may also influence receptor binding. Among those substitutions, residue 145 was shown to be a major determinant of antigenic evolution. To determine whether there are functional constraints to substitutions near the RBS and their impact on receptor binding and antigenic properties, we carried out site-directed mutagenesis experiments at the single-amino-acid level. We generated a panel of viruses carrying substitutions at residue 145 representing all 20 amino acids. Despite limited amino acid usage in nature, most substitutions at residue 145 were well tolerated without having a major impact on virus replication in vitro . All substitution mutants retained receptor binding specificity, but the substitutions frequently led to decreased receptor binding. Glycan microarray analysis showed that substitutions at residue 145 modulate binding to a broad range of glycans. Furthermore, antigenic characterization identified specific substitutions at residue 145 that altered antibody recognition. This work provides a better understanding of the functional effects of amino acid substitutions near the RBS and the interplay between receptor binding and antigenic drift. IMPORTANCE The complex and continuous antigenic evolution of IAVs remains a major hurdle for vaccine selection and effective vaccination. On the hemagglutinin (HA) of the H3N2 IAVs, the amino acid substitution N 145 K causes significant antigenic changes. We show that amino acid 145 displays remarkable amino acid plasticity in vitro , tolerating multiple amino acid substitutions, many of which have not yet been observed in nature. Mutant viruses carrying substitutions at residue 145 showed no major impairment in virus replication in the presence of lower receptor binding avidity. However, their antigenic characterization confirmed the impact of the 145 K substitution in antibody immunodominance. We provide a better understanding of the functional effects of amino acid substitutions implicated in antigenic drift and its consequences for receptor binding and antigenicity. The mutation analyses presented in this report represent a significant data set to aid and test the ability of computational approaches to predict binding of glycans and in antigenic cartography analyses.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01413-18
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2019
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  • 2
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    Online Resource
    The Molecular Determinants of Antibody Recognition and Antigenic Drift in the H3 Hemagglutinin of Swine Influenza A Virus
    American Society for Microbiology ; 2016
    In:  Journal of Virology Vol. 90, No. 18 ( 2016-09-15), p. 8266-8280
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 90, No. 18 ( 2016-09-15), p. 8266-8280
    Abstract: Influenza A virus (IAV) of the H3 subtype is an important respiratory pathogen that affects both humans and swine. Vaccination to induce neutralizing antibodies against the surface glycoprotein hemagglutinin (HA) is the primary method used to control disease. However, due to antigenic drift, vaccine strains must be periodically updated. Six of the 7 positions previously identified in human seasonal H3 (positions 145, 155, 156, 158, 159, 189, and 193) were also indicated in swine H3 antigenic evolution. To experimentally test the effect on virus antigenicity of these 7 positions, substitutions were introduced into the HA of an isogenic swine lineage virus. We tested the antigenic effect of these introduced substitutions by using hemagglutination inhibition (HI) data with monovalent swine antisera and antigenic cartography to evaluate the antigenic phenotype of the mutant viruses. Combinations of substitutions within the antigenic motif caused significant changes in antigenicity. One virus mutant that varied at only two positions relative to the wild type had a 〉 4-fold reduction in HI titers compared to homologous antisera. Potential changes in pathogenesis and transmission of the double mutant were evaluated in pigs. Although the double mutant had virus shedding titers and transmissibility comparable to those of the wild type, it caused a significantly lower percentage of lung lesions. Elucidating the antigenic effects of specific amino acid substitutions at these sites in swine H3 IAV has important implications for understanding IAV evolution within pigs as well as for improved vaccine development and control strategies in swine. IMPORTANCE A key component of influenza virus evolution is antigenic drift mediated by the accumulation of amino acid substitutions in the hemagglutinin (HA) protein, resulting in escape from prior immunity generated by natural infection or vaccination. Understanding which amino acid positions of the HA contribute to the ability of the virus to avoid prior immunity is important for understanding antigenic evolution and informs vaccine efficacy predictions based on the genetic sequence data from currently circulating strains. Following our previous work characterizing antigenic phenotypes of contemporary wild-type swine H3 influenza viruses, we experimentally validated that substitutions at 6 amino acid positions in the HA protein have major effects on antigenicity. An improved understanding of the antigenic diversity of swine influenza will facilitate a rational approach for selecting more effective vaccine components to control the circulation of influenza in pigs and reduce the potential for zoonotic viruses to emerge.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01002-16
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2016
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  • 3
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    Distribution of antibodies against influenza virus in pigs from farrow‐to‐finish farms in M inas G erais state, B razil
    Wiley ; 2015
    In:  Influenza and Other Respiratory Viruses Vol. 9, No. 3 ( 2015-05), p. 161-167
    Details
    In: Influenza and Other Respiratory Viruses, Wiley, Vol. 9, No. 3 ( 2015-05), p. 161-167
    Abstract: Swine influenza virus ( SIV ) is the cause of an acute respiratory disease that affects swine worldwide. In B razil, SIV has been identified in pigs since 1978. After the emergence of pandemic H 1 N 1 in 2009 ( H 1 N 1pdm09), few studies reported the presence of influenza virus in B razilian herds. Objectives The objective of this study was to evaluate the serological profile for influenza virus in farrow‐to‐finish pig farms in M inas G erais state, B razil. Methods Thirty farms with no SIV vaccination history were selected from the four larger pig production areas in M inas G erais state ( Z ona da M ata, T riângulo M ineiro/ A lto P aranaíba, S outh/ S outhwest and the B elo H orizonte metropolitan area). At each farm, blood samples were randomly collected from 20 animals in each production cycle category: breeding animals (sows and gilts), farrowing crate (2–3 weeks), nursery (4–7 weeks), grower pigs (8–14 weeks), and finishing pigs (15–16 weeks), with 100 samples per farm and a total of 3000 animals in this study. The samples were tested for hemagglutination inhibition activity against H 1 N 1 pandemic strain ( A /swine/ B razil/11/2009) and H 3 N 2 SIV ( A /swine/ I owa/8548‐2/98) reference strain. Results The percentages of seropositive animals for H 1 N 1pdm09 and H 3 N 2 were 26·23% and 1·57%, respectively, and the percentages of seropositive herds for both viruses were 96·6% and 13·2%, respectively. Conclusions The serological profiles differed for both viruses and among the studied areas, suggesting a high variety of virus circulation around the state, as well as the presence of seronegative animals susceptible to influenza infection and, consequently, new respiratory disease outbreaks.
    Type of Medium: Online Resource
    ISSN: 1750-2640 , 1750-2659
    URL: Issue
    URL: Article
    DOI: 10.1111/irv.2015.9.issue-3
    DOI: 10.1111/irv.12304
    Language: English
    Publisher: Wiley
    Publication Date: 2015
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  • 4
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    Canine distemper virus induces apoptosis in cervical tumor derived cell lines
    Springer Science and Business Media LLC ; 2011
    In:  Virology Journal Vol. 8, No. 1 ( 2011-12)
    Details
    In: Virology Journal, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2011-12)
    Type of Medium: Online Resource
    ISSN: 1743-422X
    URL: Article
    DOI: 10.1186/1743-422X-8-334
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2011
    detail.hit.zdb_id: 2160640-7
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  • 5
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    Novel Reassortant Human-Like H3N2 and H3N1 Influenza A Viruses Detected in Pigs Are Virulent and Antigenically Distinct from Swine Viruses Endemic to the United States
    American Society for Microbiology ; 2015
    In:  Journal of Virology Vol. 89, No. 22 ( 2015-11-15), p. 11213-11222
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 89, No. 22 ( 2015-11-15), p. 11213-11222
    Abstract: Human-like swine H3 influenza A viruses (IAV) were detected by the USDA surveillance system. We characterized two novel swine human-like H3N2 and H3N1 viruses with hemagglutinin (HA) genes similar to those in human seasonal H3 strains and internal genes closely related to those of 2009 H1N1 pandemic viruses. The H3N2 neuraminidase (NA) was of the contemporary human N2 lineage, while the H3N1 NA was of the classical swine N1 lineage. Both viruses were antigenically distant from swine H3 viruses that circulate in the United States and from swine vaccine strains and also showed antigenic drift from human seasonal H3N2 viruses. Their pathogenicity and transmission in pigs were compared to those of a human H3N2 virus with a common HA ancestry. Both swine human-like H3 viruses efficiently infected pigs and were transmitted to indirect contacts, whereas the human H3N2 virus did so much less efficiently. To evaluate the role of genes from the swine isolates in their pathogenesis, reverse genetics-generated reassortants between the swine human-like H3N1 virus and the seasonal human H3N2 virus were tested in pigs. The contribution of the gene segments to virulence was complex, with the swine HA and internal genes showing effects in vivo . The experimental infections indicate that these novel H3 viruses are virulent and can sustain onward transmission in pigs, and the naturally occurring mutations in the HA were associated with antigenic divergence from H3 IAV from humans and swine. Consequently, these viruses could have a significant impact on the swine industry if they were to cause more widespread outbreaks, and the potential risk of these emerging swine IAV to humans should be considered. IMPORTANCE Pigs are important hosts in the evolution of influenza A viruses (IAV). Human-to-swine transmissions of IAV have resulted in the circulation of reassortant viruses containing human-origin genes in pigs, greatly contributing to the diversity of IAV in swine worldwide. New human-like H3N2 and H3N1 viruses that contain a mix of human and swine gene segments were recently detected by the USDA surveillance system. The human-like viruses efficiently infected pigs and resulted in onward airborne transmission, likely due to the multiple changes identified between human and swine H3 viruses. The human-like swine viruses are distinct from contemporary U.S. H3 swine viruses and from the strains used in swine vaccines, which could have a significant impact on the swine industry due to a lack of population immunity. Additionally, public health experts should consider an appropriate assessment of the risk of these emerging swine H3 viruses for the human population.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01675-15
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2015
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  • 6
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    Antigenic mapping of the hemagglutinin of the H9 subtype influenza A viruses using sera from Japanese quail ( Coturnix c. japonica )
    American Society for Microbiology ; 2023
    In:  Journal of Virology
    Details
    In: Journal of Virology, American Society for Microbiology
    Abstract: Determining the relevant amino acids involved in antigenic drift on the surface protein hemagglutinin (HA) is critical to understand influenza virus evolution and efficient assessment of vaccine strains relative to current circulating strains. We used antigenic cartography to generate an antigenic map of the H9 hemagglutinin (HA) using sera produced in one of the most relevant minor poultry species, Japanese quail. Key antigenic positions were identified and tested to confirm their impact on the antigenic profile. This work provides a better understanding of the antigenic diversity of the H9 HA as it relates to reactivity to quail sera and will facilitate a rational approach for selecting more efficacious vaccines against poultry-origin H9 influenza viruses in minor poultry species.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/jvi.00743-23
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2023
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  • 7
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    Genetic characterization of influenza virus circulating in Brazilian pigs during 2009 and 2010 reveals a high prevalence of the pandemic H1N1 subtype
    Wiley ; 2013
    In:  Influenza and Other Respiratory Viruses Vol. 7, No. 5 ( 2013-09), p. 783-790
    Details
    In: Influenza and Other Respiratory Viruses, Wiley, Vol. 7, No. 5 ( 2013-09), p. 783-790
    Abstract: Influenza A viruses circulating in pigs in Brazil are still not characterized, and only limited data are available about swine influenza epidemiology in the country. Therefore, we characterized the hemagglutinin ( HA ) and neuraminidase ( NA ) genes of influenza viruses isolated from Brazilian pigs. We also evaluated one case of probable swine‐to‐human transmission. Methods Twenty influenza viruses isolated from pigs during 2009–2010 in five Brazilian states (Minas Gerais, Sao Paulo, Parana, Rio Grande do Sul, and Mato Grosso) were used. One human isolate, from a technician who became ill after visiting a swineherd going through a respiratory disease outbreak, was also used in the study. Phylogenetic analysis for the HA and NA genes and hemagglutinin amino acid sequence alignment were performed. Results All isolates clustered with pandemic H1N1 2009 (pH1N1) viruses and appeared to have a common ancestor. Genetic diversity was higher in the HA than in the NA gene, and the amino acid substitution S203T in one of HA 's antigenic sites was found in most of the samples. The human isolate was more related to swine isolates from the same herd visited by the technician than to other human isolates, suggesting swine‐to‐human transmission. Conclusion Our results show that pH 1N1 was disseminated and the predominant subtype in Brazilian pigs in 2009–2010.
    Type of Medium: Online Resource
    ISSN: 1750-2640 , 1750-2659
    URL: Issue
    URL: Article
    DOI: 10.1111/irv.2013.7.issue-5
    DOI: 10.1111/irv.12072
    Language: English
    Publisher: Wiley
    Publication Date: 2013
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  • 8
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    Comparative virulence of wild-type H1N1pdm09 influenza A isolates in swine
    Elsevier BV ; 2015
    In:  Veterinary Microbiology Vol. 176, No. 1-2 ( 2015-03), p. 40-49
    Details
    In: Veterinary Microbiology, Elsevier BV, Vol. 176, No. 1-2 ( 2015-03), p. 40-49
    Type of Medium: Online Resource
    ISSN: 0378-1135
    URL: Article
    DOI: 10.1016/j.vetmic.2014.12.021
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2015
    detail.hit.zdb_id: 1498996-7
    SSG: 22
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  • 9
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    Comparison of Adjuvanted-Whole Inactivated Virus and Live-Attenuated Virus Vaccines against Challenge with Contemporary, Antigenically Distinct H3N2 Influenza A Viruses
    American Society for Microbiology ; 2018
    In:  Journal of Virology Vol. 92, No. 22 ( 2018-11-15)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 92, No. 22 ( 2018-11-15)
    Abstract: Influenza A viruses in swine (IAV-S) circulating in the United States of America are phylogenetically and antigenically distinct. A human H3 hemagglutinin (HA) was introduced into the IAV-S gene pool in the late 1990s, sustained continued circulation, and evolved into five monophyletic genetic clades, H3 clades IV-A to -E, after 2009. Across these phylogenetic clades, distinct antigenic clusters were identified, with three clusters (cyan, red, and green antigenic cluster) among the most frequently detected antigenic phenotypes (Abente EJ, Santos J, Lewis NS, Gauger PC, Stratton J, et al. J Virol 90:8266–8280, 2016, https://doi.org/10.1128/JVI.01002-16 ). Although it was demonstrated that antigenic diversity of H3N2 IAV-S was associated with changes at a few amino acid positions in the head of the HA, the implications of this diversity for vaccine efficacy were not tested. Using antigenically representative H3N2 viruses, we compared whole inactivated virus (WIV) and live-attenuated influenza virus (LAIV) vaccines for protection against challenge with antigenically distinct H3N2 viruses in pigs. WIV provided partial protection against antigenically distinct viruses but did not prevent virus replication in the upper respiratory tract. In contrast, LAIV provided complete protection from disease and virus was not detected after challenge with antigenically distinct viruses. IMPORTANCE Due to the rapid evolution of the influenza A virus, vaccines require continuous strain updates. Additionally, the platform used to deliver the vaccine can have an impact on the breadth of protection. Currently, there are various vaccine platforms available to prevent influenza A virus infection in swine, and we experimentally tested two: adjuvanted-whole inactivated virus and live-attenuated virus. When challenged with an antigenically distinct virus, adjuvanted-whole inactivated virus provided partial protection, while live-attenuated virus provided effective protection. Additional strategies are required to broaden the protective properties of inactivated virus vaccines, given the dynamic antigenic landscape of cocirculating strains in North America, whereas live-attenuated vaccines may require less frequent strain updates, based on demonstrated cross-protection. Enhancing vaccine efficacy to control influenza infections in swine will help reduce the impact they have on swine production and reduce the risk of swine-to-human transmission.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.01323-18
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2018
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  • 10
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    Flexibility In Vitro of Amino Acid 226 in the Receptor-Binding Site of an H9 Subtype Influenza A Virus and Its Effect In Vivo on Virus Replication, Tropism, and Transmission
    American Society for Microbiology ; 2019
    In:  Journal of Virology Vol. 93, No. 6 ( 2019-03-15)
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 93, No. 6 ( 2019-03-15)
    Abstract: Influenza A viruses (IAVs) remain a significant public health threat, causing more than 300,000 hospitalizations in the United States during the 2015–2016 season alone. While only a few IAVs of avian origin have been associated with human infections, the ability of these viruses to cause zoonotic infections further increases the public health risk of influenza. Of these, H9N2 viruses in Asia are of particular importance as they have contributed internal gene segments to other emerging zoonotic IAVs. Notably, recent H9N2 viruses have acquired molecular markers that allow for a transition from avian-like to human-like terminal sialic acid (SA) receptor recognition via a single amino acid change at position 226 (H3 numbering), from glutamine (Q226) to leucine (L226), within the hemagglutinin (HA) receptor-binding site (RBS). We sought to determine the plasticity of amino acid 226 and the biological effects of alternative amino acids on variant viruses. We created a library of viruses with the potential of having any of the 20 amino acids at position 226 on a prototypic H9 HA subtype IAV. We isolated H9 viruses that carried naturally occurring amino acids, variants found in other subtypes, and variants not found in any subtype at position 226. Fitness studies in quails revealed that some natural amino acids conferred an in vivo replication advantage. This study shows the flexibility of position 226 of the HA of H9 influenza viruses and the resulting effect of single amino acid changes on the phenotype of variants in vivo and in vitro . IMPORTANCE A single amino acid change at position 226 in the hemagglutinin (HA) from glutamine (Q) to leucine (L) has been shown to play a key role in receptor specificity switching in various influenza virus HA subtypes, including H9. We tested the flexibility of amino acid usage and determined the effects of such changes. The results reveal that amino acids other than L226 and Q226 are well tolerated and that some amino acids allow for the recognition of both avian and human influenza virus receptors in the absence of other changes. Our results can inform better avian influenza virus surveillance efforts as well as contribute to rational vaccine design and improve structural molecular dynamics algorithms.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.02011-18
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2019
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