Modified Sialic Acids on Mucus and Erythrocytes Inhibit Influenza A Virus Hemagglutinin and Neuraminidase Functions

Barnard, Karen N.; Alford-Lawrence, Brynn K.; Buchholz, David W.; Wasik, Brian R.; LaClair, Justin R.; Yu, Hai; Honce, Rebekah; Rühl, Stefan; Pajic, Petar; Daugherity, Erin K.; Chen, Xi; Schultz‐Cherry, Stacey; Aguilar, Hector C.; Varki, Ajit; Parrish, Colin R.

doi:10.1128/jvi.01567-19

Cited by 44 publications

(48 citation statements)

References 91 publications

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“…Similarly, we found that WT H1, H2, and H4 HAs bind chicken, but not horse, erythrocytes in the hemagglutination assay (S2 Fig). Contrarily, we observed that WT avian H7 HAs bound both chicken (NeuAc [7,8]) and horse (mainly NeuGc [11,13,14]) erythrocytes and tracheal tissue while binding specifically to NeuAc on the glycan microarray. This distinguishes these H7 viruses from other subtypes of influenza A.…”

Section: Discussionmentioning

confidence: 69%

“…This distinguishes these H7 viruses from other subtypes of influenza A. Possibly, the presence of NeuAc on horse erythrocytes and tracheal tissue, although estimated to be less than 10% of the total sialic acids [11,13,14], is sufficient to be bound by the WT avian H7 HAs. Additionally, the residual NeuAc-binding of the mutant avian H7 HAs may explain the binding to chicken erythrocytes and tissue.…”

Section: Discussionmentioning

confidence: 98%

“…While only binding NeuAc on the glycan array, the wild-type (WT) H7tu agglutinates both chicken erythrocytes, which contain only NeuAc [7,8], and horse erythrocytes, which contain mainly NeuGc [11,13,14] (Fig 4A). Therefore, a loss of binding to chicken erythrocytes would indicate a loss of NeuAc-binding.…”

Section: No Binding Specificity To Avian or Equine Erythrocytes And Tmentioning

confidence: 99%

“…For instance, pig trachea contains an equal amount of NeuAc and NeuGc, while 90% of the sialic acids on equine trachea and erythrocytes is NeuGc [11][12][13][14]. The high NeuGc content in horses may explain why equine H7N7 viruses are the only known influenza A viruses that bind α2,3-linked NeuGc [15,16].…”

Section: Introductionmentioning

confidence: 99%

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N-glycolylneuraminic acid binding of avian H7 influenza A viruses

Spruit

Zhu

Broszeit

et al. 2020

Preprint

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Influenza A viruses initiate infection by binding to glycans with terminal sialic acids present on the cell surface. Hosts of influenza A viruses variably express two major forms of sialic acid, N-acetylneuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGc). NeuGc is produced in the majority of mammals including horses, pigs, and mice, but is absent in humans, ferrets, and birds. Intriguingly, the only known naturally occurring influenza A viruses that exclusively bind NeuGc are the extinct highly pathogenic equine H7N7 viruses. We determined the crystal structure of a representative equine H7 hemagglutinin (HA) in complex with its NeuGc ligand and observed a high similarity in the receptor-binding domain with an avian H7 HA. To determine the molecular basis for NeuAc and NeuGc specificity, we performed systematic mutational analyses, based on the structural insights, on two distant avian H7 HAs. We found that mutation A135E is key for binding α2,3-linked NeuGc but does not abolish NeuAc binding. Interestingly, additional mutations S128T, I130V, or a combination of T189A and K193R, converted from NeuAc to NeuGc specificity as determined by glycan microarrays. However, specific binding to NeuGc-terminal glycans on our glycan array did not always correspond with full NeuGc specificity on chicken and equine erythrocytes and tracheal epithelium sections. Phylogenetic analysis of avian and equine H7 HAs that investigated the amino acids at positions 128, 130, 135, 189, and 193 reveals a clear distinction between equine and avian residues. The highest variability in amino acids (four different residues) is observed at key position 135, of which only the equine glutamic acid leads to binding of NeuGc. The results demonstrate that avian H7 viruses, although genetically distinct from equine H7 viruses, can bind NeuGc after the introduction of two to three mutations, providing insights into the adaptation of H7 viruses to NeuGc receptors.Author summaryInfluenza A viruses cause millions of cases of severe illness and deaths annually. To initiate infection and replicate, the virus first needs to bind to a structure on the cell surface, like a key fitting in a lock. For influenza A virus, these ‘keys’ (receptors) on the cell surface are chains of sugar molecules (glycans). The terminal sugar on these glycans is often either N-acetylneuraminic acid (NeuAc) or N-glycolylneuraminic acid (NeuGc). Most influenza A viruses bind NeuAc, but a small minority binds NeuGc. NeuGc is present in species like horses, pigs, and mice, but not in humans, ferrets, and birds. Therefore, NeuGc binding could be a determinant of an Influenza A virus species barrier. Here, we investigated the molecular determinants of NeuGc specificity and the origin of viruses that bind NeuGc.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 98%

Section: No Binding Specificity To Avian or Equine Erythrocytes And Tmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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N-glycolylneuraminic acid binding of avian H7 influenza A viruses

Spruit

Zhu

Broszeit

et al. 2020

Preprint

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“…While HA mediates virion-SA attachment and fusion, NA is responsible for terminal SA residues cleavage [19]. N-glycolyl and O-acetyl modification of SA could reduce binding affinities of both NA and HA [20]. In addition, NA possesses at least two calcium binding sites [21].…”

Section: Iav Viral Proteinsmentioning

confidence: 99%

Host–Virus Interaction: How Host Cells Defend against Influenza A Virus Infection

Zhang

Cao

2020

Viruses

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Influenza A viruses (IAVs) are highly contagious pathogens infecting human and numerous animals. The viruses cause millions of infection cases and thousands of deaths every year, thus making IAVs a continual threat to global health. Upon IAV infection, host innate immune system is triggered and activated to restrict virus replication and clear pathogens. Subsequently, host adaptive immunity is involved in specific virus clearance. On the other hand, to achieve a successful infection, IAVs also apply multiple strategies to avoid be detected and eliminated by the host immunity. In the current review, we present a general description on recent work regarding different host cells and molecules facilitating antiviral defenses against IAV infection and how IAVs antagonize host immune responses.

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Exploring Mechanisms of Lipid Nanoparticle‐Mucus Interactions in Healthy and Cystic Fibrosis Conditions

Tafech,

Rokhforouz,

Leung

et al. 2024

Adv Healthcare Materials

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Mucus forms the first defense line of human lungs, and as such hampers the efficient delivery of therapeutics to the underlying epithelium. This holds particularly true for genetic cargo such as CRISPR‐based gene editing tools which cannot readily surmount the mucosal barrier. While lipid nanoparticles (LNPs) emerged as versatile non‐viral gene delivery systems that could help overcome the delivery challenge, many knowledge gaps remain, especially for diseased states such as cystic fibrosis (CF). This study provides fundamental insights into Cas9 mRNA or ribonucleoprotein‐loaded LNP‐mucus interactions in healthy and diseased states by assessing the impact of the genetic cargo, mucin sialylation, mucin concentration, ionic strength, pH, and polyethylene glycol (PEG) concentration and nature on LNP diffusivity leveraging experimental approaches and Brownian dynamics simulations. Taken together, this study identifies key mucus and LNP characteristics that are critical to enabling a rational LNP design for transmucosal delivery.This article is protected by copyright. All rights reserved

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Modified Sialic Acids on Mucus and Erythrocytes Inhibit Influenza A Virus Hemagglutinin and Neuraminidase Functions

Cited by 44 publications

References 91 publications

N-glycolylneuraminic acid binding of avian H7 influenza A viruses

N-glycolylneuraminic acid binding of avian H7 influenza A viruses

Host–Virus Interaction: How Host Cells Defend against Influenza A Virus Infection

Exploring Mechanisms of Lipid Nanoparticle‐Mucus Interactions in Healthy and Cystic Fibrosis Conditions

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