Influenza as a molecular walker - PubMed (original) (raw)

Review

. 2019 Nov 14;11(1):27-36.

doi: 10.1039/c9sc05149j. eCollection 2020 Jan 7.

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Review

Influenza as a molecular walker

P H Erik Hamming et al. Chem Sci. 2019.

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Abstract

The surface of the influenza virus is decorated with the receptor-binding protein hemagglutinin (HA) and the receptor-cleaving enzyme neuraminidase (NA). HA is responsible for host cell recognition, while NA prevents aggregation and entrapment, but the intricate mechanism of how the functions of these glycoproteins cooperate and how they are regulated by mutational responses to environmental pressures remains unclear. Recently, several groups have described the motion of influenza over surfaces and reported that this motion is inhibited by NA inhibitors. We argue that the motion of influenza resembles the motility of artificial receptor-cleaving particles called "molecular spiders". The cleaving of receptors by this type of molecular walkers leads to self-avoiding motion across a surface. When the binding and cleaving rates of molecular spiders are balanced, they move both rapidly and efficiently. The studies of molecular spiders offer new insights into the functional balance of HA and NA, but they do not address the asymmetric distribution of HA and NA on the surface of influenza. We propose that receptor-cleaving molecular walkers could play an important role in the further investigation of the motility of influenza viruses.

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Figures

Fig. 1

Fig. 1. Mechanism for directional motility in molecular spiders., (a) A molecular spider consists of a rigid body with several legs. The legs bind to receptors on a surface, cleaving them as they go. The legs can bind to a cleaved receptor, but have a lower residence time. (b) The difference in residence time can lead to a bias in movement. At _t_0, the spider is attached at the boundary between fresh and cleaved receptors with one leg. At _t_1, the legs are more likely to be bound to fresh than to cleaved receptors due to the difference in residence times. At _t_2, the first leg detaches and leaves a cleaved receptor behind, shifting the boundary. (c) The spider is either at the boundary and moving with a bias towards fresh receptors, or the spider is in a patch of cleaved receptors where all legs have low residence time and diffusion is fast.

Fig. 2

Fig. 2. Main design parameters in molecular spiders. (a) The number of legs (n) of a spider and the length of each leg (L) define the boundary state of the spider. (b) Molecular spiders can walk using an inchworm (I) or hand-over-hand (II) motif. (c) The kinetics of interaction between the substrate and an individual leg.

Fig. 3

Fig. 3. (a) Hemagglutinin (HA) is a trimeric protein that binds to sialic acid-terminated glycans in a reversible manner. (b) Neuraminidase (NA) is a tetrameric protein that binds and cleaves sialic acid-terminated glycans. (c) HA and NA are present on the surface of influenza in high copy numbers, approximately in a 6 : 1 ratio.

Fig. 4

Fig. 4. Mechanism for virus motion proposed by Sakai et al. (a) Influenza binds tightly to a surface with multiple HA-receptor interactions. (b) NA cleaves receptors, which decreases the number of interactions and initiates motility. (c) A loosely attached virus performs crawling and gliding motions by iterative association and dissociation of HA-receptor interactions, until it reaches a site where it can form multiple interactions and again bind tightly to the surface. Reprinted from ref. 15, with permission from Springer Nature, licensed under CC BY 4.0.

Fig. 5

Fig. 5. Motility of influenza is driven by NA activity. De Haan et al. partially blocked receptors on BLI sensors with viruses that had inactive NA and then exposed the sensors to a virus with active NA. One sensor (in blue) was protected with the NA inhibitor oseltamivir carboxylate (OC), one sensor (in red) was only locally blocked by the NA-inactive virus, and one sensor (in green) was left fully unprotected. After regeneration of the sensors, exposure to new virus showed that receptors were cleaved from all unprotected areas. Adapted from ref. 16 with permission from Public Library of Sciences, licensed under CC BY 4.0.

Fig. 6

Fig. 6. By labelling HA, NA and cleaved receptors, Vahey and Fletcher showed that the asymmetric organization of HA and NA imparts directional motility in filamentous viruses. Reprinted from ref. 18 with permission from eLife Sciences Publications, licensed under CC BY 4.0.

Fig. 7

Fig. 7. Block et al. tracked influenza viruses on supported lipid bilayers to quantify the number of interactions with glycolipids. They observed elevated _k_off values for 1/D ∼ 5 s μm–2, which decreased with added NA inhibitor. Reprinted with permission from ref. 17. Copyright 2019 American Chemical Society.

Fig. 8

Fig. 8. (a) Self-avoiding walking gives rise to an efficient search pattern to find clathrin-coated pits. (b) The motility of molecular spiders is biased towards a higher density of receptors.

Fig. 9

Fig. 9. (a) The structure of the mucus in human airways as proposed by Rubinstein et al. (b) The function of molecular walking of influenza in crossing the mucus. (I) When there is no interaction, particles are repelled by the charged brush. (II) Particles that have an affinity for sialic acid are entrapped. (III) Influenza, which binds and cleaves sialic acid, can walk through the mucus.

None

P. H. (Erik) Hamming

None

Nico J. Overeem

None

Jurriaan Huskens

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