Human Influenza Virus Hemagglutinins Contain Conserved Oligomannose N-Linked Glycans Allowing Potent Neutralization by Lectins

Thompson, Andrew J.; Cao, Liwei; Ma, Yuanhui; Wang, Xiaoning; Diedrich, Jolene K.; Kikuchi, Chika; Willis, Shelby; Worth, Charli; McBride, Ryan; Yates, John R.; Paulson, James C.

doi:10.1016/j.chom.2020.03.009

Cited by 33 publications

(28 citation statements)

References 73 publications

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“…Indeed, besides H3N2 HAs and HIV-1 Env, 2G12 has been purported to bind SARS-CoV-2 S by recognizing high mannose glycans on the S2 subunit [ 64 ]. Mannose clusters on surface antigens can also be recognized or captured by various lectins, such as human mannose binding lectin (MBL) or DC-SIGN [ 65 – 67 ]. Similar to our finding of high mannose glycans near the RBS on H3 HA, some high mannose glycans are also found near the RBS of the glycoprotein of Lassa virus [ 44 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

A cross-neutralizing antibody between HIV-1 and influenza virus

Lee

Watanabe

et al. 2021

PLoS Pathog

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Incessant antigenic evolution enables the persistence and spread of influenza virus in the human population. As the principal target of the immune response, the hemagglutinin (HA) surface antigen on influenza viruses continuously acquires and replaces N-linked glycosylation sites to shield immunogenic protein epitopes using host-derived glycans. Anti-glycan antibodies, such as 2G12, target the HIV-1 envelope protein (Env), which is even more extensively glycosylated and contains under-processed oligomannose-type clusters on its dense glycan shield. Here, we illustrate that 2G12 can also neutralize human seasonal influenza A H3N2 viruses that have evolved to present similar oligomannose-type clusters on their HAs from around 20 years after the 1968 pandemic. Using structural biology and mass spectrometric approaches, we find that two N-glycosylation sites close to the receptor binding site (RBS) on influenza hemagglutinin represent the oligomannose cluster recognized by 2G12. One of these glycan sites is highly conserved in all human H3N2 strains and the other emerged during virus evolution. These two N-glycosylation sites have also become crucial for fitness of recent H3N2 strains. These findings shed light on the evolution of the glycan shield on influenza virus and suggest 2G12-like antibodies can potentially act as broad neutralizers to target human enveloped viruses.

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Section: Discussionmentioning

confidence: 99%

A cross-neutralizing antibody between HIV-1 and influenza virus

Lee

Watanabe

et al. 2021

PLoS Pathog

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“…The binding of influenza A viruses to cells are not restricted to the recognition of sialic acids by the receptor binding site (RBS) of HA. It has been reported that influenza A viruses can bind to lectin receptors, suggesting that lectin-HA interaction might be involved in virus attachment and subsequent viral entry [ 37 , 38 ]. We previously addressed the role of DC-SIGN in H5N1 AIVs infection and demonstrated that DC-SIGN can serve as an attachment molecule to facilitate H5N1 infection [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Important N-Linked Glycosylation Sites in the Hemagglutinin Protein and Their Functional Impact on DC-SIGN Mediated Avian Influenza H5N1 Infection

Yang,

Huang,

Wang

et al. 2021

IJMS

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DC-SIGN, a C-type lectin mainly expressed in dendritic cells (DCs), has been reported to mediate several viral infections. We previously reported that DC-SIGN mediated H5N1 influenza A virus (AIVs) infection, however, the important DC-SIGN interaction with N-glycosylation sites remain unknown. This study aims to identify the optimal DC-SIGN interacting N-glycosylation sites in HA proteins of H5N1-AIVs. Results from NetNGlyc program analyzed the H5 hemagglutinin sequences of isolates during 2004–2020, revealing that seven and two conserved N-glycosylation sites were detected in HA1 and HA2 domain, respectively. A lentivirus pseudotyped A/Vietnam/1203/04 H5N1 envelope (H5N1-PVs) was generated which displayed an abundance of HA5 proteins on the virions via immuno-electron microscope observation. Further, H5N1-PVs or reverse-genetics (H5N1-RG) strains carrying a serial N-glycosylated mutation was generated by site-directed mutagenesis assay. Human recombinant DC-SIGN (rDC-SIGN) coated ELISA showed that H5N1-PVs bound to DC-SIGN, however, mutation on the N27Q, N39Q, and N181Q significantly reduced this binding (p < 0.05). Infectivity and capture assay demonstrated that N27Q and N39Q mutations significantly ameliorated DC-SIGN mediated H5N1 infection. Furthermore, combined mutations (N27Q&N39Q) significantly waned the interaction on either H5N1-PVs or -RG infection in cis and in trans (p < 0.01). This study concludes that N27 and N39 are two essential N-glycosylation contributing to DC-SIGN mediating H5N1 infection.

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“…A recent study has shown that N-glycosylation sites are added to HAs of seasonal influenza virus at discrete 5-to-7-year intervals, with an upper limit of~6 and~8 glycans in the HA1 globular head domains of H1N1 and H3N2, respectively [92]. The glycan form, occupancy, and heterogeneity at each N-glycosylation site on HA can be probed by mass spectrometry [93,94]. Moreover, some of the N-glycans on HA can be observed by X-ray crystallography and cryo-EM [9,64].…”

Section: Antibodies To Influenza Hamentioning

confidence: 99%

Structural Biology of Influenza Hemagglutinin: An Amaranthine Adventure

Wilson

2020

Viruses

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Hemagglutinin (HA) glycoprotein is an important focus of influenza research due to its role in antigenic drift and shift, as well as its receptor binding and membrane fusion functions, which are indispensable for viral entry. Over the past four decades, X-ray crystallography has greatly facilitated our understanding of HA receptor binding, membrane fusion, and antigenicity. The recent advances in cryo-EM have further deepened our comprehension of HA biology. Since influenza HA constantly evolves in natural circulating strains, there are always new questions to be answered. The incessant accumulation of knowledge on the structural biology of HA over several decades has also facilitated the design and development of novel therapeutics and vaccines. This review describes the current status of the field of HA structural biology, how we got here, and what the next steps might be.

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Human Influenza Virus Hemagglutinins Contain Conserved Oligomannose N-Linked Glycans Allowing Potent Neutralization by Lectins

Cited by 33 publications

References 73 publications

A cross-neutralizing antibody between HIV-1 and influenza virus

A cross-neutralizing antibody between HIV-1 and influenza virus

Identification of Important N-Linked Glycosylation Sites in the Hemagglutinin Protein and Their Functional Impact on DC-SIGN Mediated Avian Influenza H5N1 Infection

Structural Biology of Influenza Hemagglutinin: An Amaranthine Adventure

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