N-Linked Glycosylation of the Hemagglutinin Protein Influences Virulence and Antigenicity of the 1918 Pandemic and Seasonal H1N1 Influenza A Viruses

Sun, Xiangjie; Jayaraman, Akila; Maniprasad, Pavithra; Raman, Rahul; Houser, Katherine V.; Pappas, Claudia; Zeng, Hui; Sasisekharan, Ram; Katz, Jacqueline M.; Tumpey, Terrence M.

doi:10.1128/jvi.00593-13

Cited by 94 publications

(85 citation statements)

References 43 publications

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“…This observation could be related to previous works, demonstrating that an increase of the number of glycosites on the HA of H3N2 or H1N1 viruses increases their susceptibility to Supernatant Proteins D (SP-D) neutralization (Hartshorn et al, 2008;Hillaire et al, 2012;Reading et al, 2009;Sun et al, 2013;Tate et al, 2011;Vigerust et al, 2007). To clarify this point, it could be interesting to test the neutralization of our glyV viruses using recombinant SP-D proteins described in previous studies (Crouch et al, 1994;Hartshorn et al, 2008), or bronchoalveolar lavage fluids collected from naive mice.…”

Section: Discussionmentioning

confidence: 58%

Addition of N-glycosylation sites on the globular head of the H5 hemagglutinin induces the escape of highly pathogenic avian influenza A H5N1 viruses from vaccine-induced immunity

et al. 2015

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Highly pathogenic avian influenza A H5N1 viruses remain endemic in poultry in several countries and still constitute a pandemic threat. Since the early 20th century, we experienced four influenza A pandemics. H3N2 and H1N1pdm09 viruses that respectively emerged during 1968 and 2009 pandemics are still responsible for seasonal epidemics. These viruses evolve regularly by substitutions in antigenic sites of the hemagglutinin (HA), which prevent neutralization by antibodies directed against previous strains (antigenic drift). For seasonal H3N2 viruses, an addition of N-glycosylation sites (glycosites) on H3 contributed to this drift. Here, we questioned whether additional glycosites on H5 could induce an escape of H5N1 virus from neutralization, as it was observed for seasonal H3N2 viruses. Seven H5N1 mutants were produced by adding glycosites on H5. The most glycosylated virus escaped from neutralizing antibodies, in vitro and in vivo. Furthermore, a single additional glycosite was responsible for this escape.

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Section: Discussionmentioning

confidence: 58%

Addition of N-glycosylation sites on the globular head of the H5 hemagglutinin induces the escape of highly pathogenic avian influenza A H5N1 viruses from vaccine-induced immunity

et al. 2015

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“…These genetically defined viruses confirmed the importance of particular glycosylation sites (e.g., Asn 165 (Asn 181 ) for H3 and Asn 130 (Asn 144 ) for H1) in determining sensitivity to rodent [62,63] and human SP-D [29]. Recently, similar approaches confirmed that addition (to virus expressing the 1918 pandemic H1 HA) or removal (to virus expressing the H1 HA of seasonal A/Solomon Islands/2006) of glycosylation sites from the head of HA was associated with attenuated or enhanced virulence in mice, respectively [65], although sensitivity to SP-D was not addressed in this study.…”

Section: Ha Glycosylation Determines Sensitivity Of Iav To Lectinsmentioning

confidence: 99%

Playing Hide and Seek: How Glycosylation of the Influenza Virus Hemagglutinin Can Modulate the Immune Response to Infection

Tate

Job

Deng

et al. 2014

Viruses

247

205

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Seasonal influenza A viruses (IAV) originate from pandemic IAV and have undergone changes in antigenic structure, including addition of glycans to the hemagglutinin (HA) glycoprotein. The viral HA is the major target recognized by neutralizing antibodies and glycans have been proposed to shield antigenic sites on HA, thereby promoting virus survival in the face of widespread vaccination and/or infection. However, addition of glycans can also interfere with the receptor binding properties of HA and this must be compensated for by additional mutations, creating a fitness barrier to accumulation of glycosylation sites. In addition, glycans on HA are also recognized by phylogenetically ancient lectins of the innate immune system and the benefit provided by evasion of humoral immunity is balanced by attenuation of infection. Therefore, a fine balance must exist regarding the optimal pattern of HA glycosylation to offset competing pressures associated with recognition by innate defenses, evasion of humoral immunity and maintenance of virus fitness. In this review, we examine HA glycosylation patterns of IAV associated with pandemic and seasonal influenza and discuss recent advancements in our understanding of interactions between IAV glycans and components of innate and adaptive immunity.

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“…Over time, the number of glycosylation sites in circulating influenza strains has increased [50,52], presumably shielding the protein surface from antibody recognition and assisting the virus in evading host immune surveillance [50,53–56]. However, the more heavily glycosylated an HA1 domain, the more likely that its receptor binding ability will be impaired, either because the glycosylation directly blocks access to the RBS [57,58], or because it forms a shield through which short receptor glycans may not be able to penetrate.…”

Section: Impact Of Ha Glycosylation On Specificitymentioning

confidence: 99%

New insights into influenza A specificity: an evolution of paradigms

White

Hadden

et al. 2017

Current Opinion in Structural Biology

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Understanding the molecular origin of influenza receptor specificity is complicated by the paucity of quantitative affinity measurements, and the qualitative and variable nature of glycan array data. Further obstacles arise from the varied impact of viral glycosylation and the relatively narrow spectrum of biologically relevant receptors present on glycan arrays. A survey of receptor conformational properties is presented, leading to the conclusion that conformational entropy plays a key role in defining specificity, as does the newly reported ability of biantennary receptors that terminate in Siaα2-6Gal sequences to form bidentate interactions to two binding sites in a hemagglutinin trimer. Bidentate binding provides a functional explanation for the observation that Siaα2-6 receptors adopt an open-umbrella topology when bound to hemagglutinins from human-infective viruses, and calls for a reassessment of virus avidity and tissue tropism.

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N-Linked Glycosylation of the Hemagglutinin Protein Influences Virulence and Antigenicity of the 1918 Pandemic and Seasonal H1N1 Influenza A Viruses

Cited by 94 publications

References 43 publications

Addition of N-glycosylation sites on the globular head of the H5 hemagglutinin induces the escape of highly pathogenic avian influenza A H5N1 viruses from vaccine-induced immunity

Addition of N-glycosylation sites on the globular head of the H5 hemagglutinin induces the escape of highly pathogenic avian influenza A H5N1 viruses from vaccine-induced immunity

Playing Hide and Seek: How Glycosylation of the Influenza Virus Hemagglutinin Can Modulate the Immune Response to Infection

New insights into influenza A specificity: an evolution of paradigms

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