Influenza A Virus Hemagglutinin–Neuraminidase–Receptor Balance: Preserving Virus Motility

Vries, Erik de; Du, Wenjuan; Guo, Hongbo; Haan, Cornelis A. M. de

doi:10.1016/j.tim.2019.08.010

Cited by 145 publications

(151 citation statements)

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“…For influenza A virus, the existence and biological relevance of a functional balance between receptor-binding and receptor destruction is well recognized 59–62 . This balance is critical for receptor-associated virus motility through the mucus and at the cell surface 63–68 . Complete or partial loss of NA activity -whether invoked spontaneously, through reverse genetics or by viral propagation in the presence of NA inhibitors-selects for mutations around the HA receptor-binding pocket that reduce HA affinity 60,69,70 .…”

Section: Discussionmentioning

confidence: 99%

Coronavirus hemagglutinin-esterase and spike proteins co-evolve for functional balance and optimal virion avidity

Lang

et al. 2020

Preprint

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22Human coronaviruses OC43 and HKU1 are respiratory pathogen of zoonotic origin that have gained 23 worldwide distribution. OC43 apparently emerged from a bovine coronavirus (BCoV) spill-over. All 24 three viruses attach to 9-O-acetylated sialoglycans via spike protein S with hemagglutinin-esterase HE 25 acting as a receptor-destroying enzyme. In BCoV, an HE lectin domain promotes esterase activity 26 towards clustered substrates. OC43 and HKU1, however, lost HE lectin function as an adaptation to 27 humans. Replaying OC43 evolution, we knocked-out BCoV HE lectin function and performed forced 28 evolution-population d ynamics analysis. Loss of HE receptor-binding selected for second-site 29 mutations in S, decreasing S binding affinity by orders of magnitude. Irreversible HE mutations 30 selected for cooperativity in virus swarms with low-affinity S minority variants sustaining propagation 31 of high-affinity majority phenotypes. Salvageable HE mutations induced successive second-site 32 substitutions in both S and HE. Apparently, S and HE are functionally interdependent and co-evolve to 33 optimize the balance between attachment and release. This mechanism of glycan-based receptor 34 usage, entailing a concerted, fine-tuned activity of two envelope protein species, is unique among 35 CoVs, but reminiscent of that of influenza A viruses (IAVs). Apparently, general principles fundamental 36 to virion-sialoglycan interactions prompted convergent evolution of two important groups of human 37 and animal pathogens. 38(which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 39The subfamily Orthocoronavirinae comprises a group of enveloped positive-strand RNA viruses of 40 clinical and veterinary significance. Adding to the socio-economic impact of coronaviruses (CoVs) 41 already extant in humans and livestock, the emergence of 'new' CoVs through cross species 42 transmission poses an ever-looming threat to public health, animal health, and food production. 43 Seven coronaviruses are known to infect humans, but not all of them have become established. The 44 introduction of SARS CoV in 2002 from horseshoe bats with masked palm civets as incidental transient 45 hosts, was rapidly contained through quarantine measures 1 . MERS CoV, natural to dromedary camels, 46 causes a classical zoonotic infection with limited human-to-human spread 2 . December 2019, a 47 member of the species Severe acute respiratory syndrome related coronavirus (SARS-CoV), called 48 SARS-CoV-2 and 79.5% identical to the 2002 SARS CoV variant, emerged in Wuhan, China 3,4 to progress 49 to full scale pandemicity. Chances are, SARS-CoV-2 will eventually become established in the human 50 population. 51Four other respiratory coronaviruses of zoonotic origin already did succeed in becoming true human 52 viruses with world-wide distribution 5-7 . Among them are HKU1 and OC43 (subgenus Embecovirus, 53 genus Betacoronavirus), related yet distinct viruses that arose from diff...

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Section: Discussionmentioning

confidence: 99%

Coronavirus hemagglutinin-esterase and spike proteins co-evolve for functional balance and optimal virion avidity

Lang

et al. 2020

Preprint

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“…Several reports on IAV diffusion through mucus suggest interactions with mucin-associated glycans contribute to its transport behavior (13,18,37). For example, it has been shown H1N1 and H3N2 IAV adhere to human lung tissue sections and salivary mucus in a sialic acid-dependent manner (16).…”

Section: Discussionmentioning

confidence: 99%

“…Given these measurable effects of glycan binding on IAV diffusion, we next examined the impact of NA activity on IAV diffusion. Prior work has shown IAV is immobilized when NA activity is inhibited given it is not be able to cleave the SA on the mucins that IAV HA binds to (13,18). To test this, we measured IAV diffusion in human mucus in the presence of the NA inhibitor (NAI), zanamivir.…”

Section: Effect Of Iav Neuraminidase (Na) Inhibition On Iav Diffusionmentioning

confidence: 99%

“…Previous work has shown the same HA/NA machinery also plays a role in the penetration of IAV through the mucus barrier to infection (13,16,17). Specifically, prior work has shown HA on IAV binds to sialic acid within mucus, which is predominantly as ⍺-2,3 linked sialic acid on mucins (18). In order to facilitate IAV diffusion through mucus, NA activity is required for removal of sialic acid decoy receptors (17).…”

Section: Introductionmentioning

confidence: 99%

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Influenza A virus diffusion through mucus gel networks

Kaler

Iverson

Bader

et al. 2020

Preprint

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In this study, influenza A virus (IAV) and nanoparticle diffusion in human airway mucus was quantified using fluorescent video microscopy and multiple particle tracking. In previous work, it was determined that mucin-associated sialic acid acts as a decoy receptor for IAV hemagglutinin binding, and that virus passage through the mucus gel layer is facilitated through the sialic-acid cleaving enzyme, neuraminidase (NA), also present on the IAV envelope. However, our data suggests the mobility of IAV in mucus is significantly influenced by the mesh structure of the gel, as measured by nanoparticle probes, and NA activity is not required to facilitate virus passage through mucus gels. Using newly developed analyses, the binding affinity of IAV to the 3D mucus meshwork was estimated for individual virions with dissociation constants in the mM range, indicative of weak and reversible IAV-mucus interactions. We also found IAV diffusion significantly increased in mucus when treated with a mucolytic agent to break mucin-mucin disulfide bonds. In addition, IAV diffusion was significantly limited in a synthetic mucus model as crosslink density was systematically increased and network pore size was reduced. The results of this work provide important insights on how the balance of adhesive and physical barrier properties of mucus influence the dissemination of IAV within the lung microenvironment.

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“…Each NA protomer consists of a membrane-anchored amino-terminal stalk domain and the globular domain containing the catalytic site that recognizes and cleaves sialic acids from glycans (Air and Laver 1989). The name NA implies this protein has neuraminidase activity and has been shown to facilitate egress of virions from infected cells (Air 2012;de Vries et al 2020). Inhibition of this process either by small molecules or antibodies results in virus sequestration on the host cell membrane, leading to inefficient viral spread.…”

Section: Antigen Targets For Influenza Vaccinesmentioning

confidence: 99%

Next-Generation Influenza Vaccines

Kanekiyo

Graham

2020

Cold Spring Harb Perspect Med

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Most currently used conventional influenza vaccines are based on 1940s technology. Advances in vaccine immunogen design and delivery emerging over the last decade promise new options for improving influenza vaccines. In addition, new technologies for immune profiling provide better-defined immune correlates of protection and precise surrogate biomarkers for vaccine evaluations. Major technological advances include single-cell analysis, high-throughput antibody discovery, next-generation sequencing of antibody gene transcripts, antibody ontogeny, structure-guided immunogen design, nanoparticle display, delivery and formulation options, and better adjuvants. In this review, we provide our prospective outlook for improved influenza vaccines in the foreseeable future.

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Influenza A Virus Hemagglutinin–Neuraminidase–Receptor Balance: Preserving Virus Motility

Cited by 145 publications

References 132 publications

Coronavirus hemagglutinin-esterase and spike proteins co-evolve for functional balance and optimal virion avidity

Coronavirus hemagglutinin-esterase and spike proteins co-evolve for functional balance and optimal virion avidity

Influenza A virus diffusion through mucus gel networks

Next-Generation Influenza Vaccines

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