Single Particle Analysis of H3N2 Influenza Entry Differentiates the Impact of the Sialic Acids (Neu5Ac and Neu5Gc) on Virus Binding and Membrane Fusion

Chien, Yu-An Annie; Alford, Brynn K; Wasik, Brian R.; Weichert, Wendy S.; Parrish, Colin R.; Daniel, Susan

doi:10.1128/jvi.01463-22

Cited by 4 publications

(2 citation statements)

References 42 publications

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“…Our experiments, showing the effect of V/HN-LV infection on both desialylated HEK293FT cells and monkey CMAH-overexpressing HEK293FT cells, revealed that SeV-HN proteins preferentially utilize Neu5Ac to support viral entry into host cells. For influenza viruses, a similar pattern was reported, which was that Neu5Gc terminated glycoconjugates act as a decoy or low-binding receptor for the hemagglutinin (HA) domain [61,62]. We also observed that V/HN-LV transduction efficiency was decreased by neuraminidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA) treatment, which suggests the relative contribution of the neuraminidase of SeV-HN for the viral entry.…”

Section: Discussionsupporting

confidence: 81%

The Dual-Pseudotyped Lentiviral Vector with VSV-G and Sendai Virus HN Enhances Infection Efficiency through the Synergistic Effect of the Envelope Proteins

Jargalsaikhan,

Muto,

Been

et al. 2024

Viruses

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A gene delivery system utilizing lentiviral vectors (LVs) requires high transduction efficiency for successful application in human gene therapy. Pseudotyping allows viral tropism to be expanded, widening the usage of LVs. While vesicular stomatitis virus G (VSV-G) single-pseudotyped LVs are commonly used, dual-pseudotyping is less frequently employed because of its increased complexity. In this study, we examined the potential of phenotypically mixed heterologous dual-pseudotyped LVs with VSV-G and Sendai virus hemagglutinin-neuraminidase (SeV-HN) glycoproteins, termed V/HN-LV. Our findings demonstrated the significantly improved transduction efficiency of V/HN-LV in various cell lines of mice, cynomolgus monkeys, and humans compared with LV pseudotyped with VSV-G alone. Notably, V/HN-LV showed higher transduction efficiency in human cells, including hematopoietic stem cells. The efficient incorporation of wild-type SeV-HN into V/HN-LV depended on VSV-G. SeV-HN removed sialic acid from VSV-G, and the desialylation of VSV-G increased V/HN-LV infectivity. Furthermore, V/HN-LV acquired the ability to recognize sialic acid, particularly N-acetylneuraminic acid on the host cell, enhancing LV infectivity. Overall, VSV-G and SeV-HN synergistically improve LV transduction efficiency and broaden its tropism, indicating their potential use in gene delivery.

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Section: Discussionsupporting

confidence: 81%

The Dual-Pseudotyped Lentiviral Vector with VSV-G and Sendai Virus HN Enhances Infection Efficiency through the Synergistic Effect of the Envelope Proteins

Jargalsaikhan,

Muto,

Been

et al. 2024

Viruses

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“…Equine IAVs are the only IAVs that have a higher preference for Neu5Gc than Neu5Ac ( Broszeit, 2019 ; Gambaryan et al., 2012 ) however, a single amino acid substitution can improve the binding preference for Neu5Gc in IAV isolates from turkeys, chickens, and dogs ( Spruit et al., 2022 ; Wen et al., 2018 ). Furthermore, a recent study showed that a change of binding affinity from Neu5Ac to Neu5Gc does not affect the fusion of IAV with the endosomal membrane because the fusion is only dependent on the H2 subunit ( Chien, 2023 ). The difference in SA preference between avian IAV isolates (SA-α2,3) and the human or swine IAV isolates (SA-α2,6) constitute one of the most important species barriers between IAV in birds and mammalians ( Bourret, 2018 ), but since human and swine IAV isolates have a similar preference for the SA-α2,6 receptor, this cannot explain why most swine-adapted IAVs have a decreased ability to infect humans.…”

Section: Introductionmentioning

confidence: 99%

The avian influenza A virus receptor SA-α2,3-Gal is expressed in the porcine nasal mucosa sustaining the pig as a mixing vessel for new influenza viruses

Kristensen,

Larsen,

Trebbien

et al. 2024

Virus Research

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Cell binding, uptake and infection of influenza A virus using recombinant antibody-based receptors

Adu,

Borau,

Früh

et al. 2024

Preprint

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Human and avian influenza A viruses bind to sialic acid (Sia) receptors on cells as their primary receptors, and this results in endocytic uptake of the virus. While the role of Sia on glycoproteins and/or glycolipids for virus entry is crucial, the roles of the carrier proteins are still not well understood. Furthermore, it is still unclear how receptor binding leads to infection, including whether the receptor plays a structural or other roles beyond being a simple tether. To enable the investigation of the receptor binding and cell entry processes in a more controlled manner, we have designed a protein receptor for pandemic H1 influenza A viruses. The engineered receptor possesses the binding domains of an anti-HA antibody prepared as a single chain variable fragment (scFv) fused with the stalk, transmembrane and cytoplasmic sequences of the feline transferrin receptor type-1 (fTfR). When expressed in cells that lack efficient display of Sia due to a knockout of the Slc35A1gene which encodes for the Solute Carrier Family 35 transporter (SLC35A1), the anti-H1 receptor was displayed on the cell surface, bound virus or hemagglutinin proteins, and the virus was efficiently endocytosed into the cells. Infection occurred at similar levels to those seen after Sia reconstitution, and treatment with clathrin-mediated endocytosis (CME) inhibitors significantly reduced viral entry.

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Single Particle Analysis of H3N2 Influenza Entry Differentiates the Impact of the Sialic Acids (Neu5Ac and Neu5Gc) on Virus Binding and Membrane Fusion

Abstract: Influenza A virus (IAV) infections continue to threaten human health, causing over 300,000 deaths yearly. IAV infection is initiated by the binding of influenza glycoprotein hemagglutinin (HA) to host cell sialic acids (Sias) and the subsequent viral-host membrane fusion.

Cited by 4 publications

References 42 publications

The Dual-Pseudotyped Lentiviral Vector with VSV-G and Sendai Virus HN Enhances Infection Efficiency through the Synergistic Effect of the Envelope Proteins

The Dual-Pseudotyped Lentiviral Vector with VSV-G and Sendai Virus HN Enhances Infection Efficiency through the Synergistic Effect of the Envelope Proteins

The avian influenza A virus receptor SA-α2,3-Gal is expressed in the porcine nasal mucosa sustaining the pig as a mixing vessel for new influenza viruses

Cell binding, uptake and infection of influenza A virus using recombinant antibody-based receptors

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