Receptor specificity of erythrocytes from different species related to swine, equine, avian and human influenza viruses

ABSTRACT Although current H5N1 highly pathogenic avian influenza viruses (HPAIV) are inefficiently transmitted to humans, infected individuals can suffer from severe disease, often progressing rapidly to acute respiratory distress syndrome and multiorgan failure. This is in contrast with the situation with human influenza viruses, which in immunocompetent individuals usually cause only a respiratory disease which is less aggressive than that observed with avian H5N1 viruses. While the biological basis of inefficient transmission is well documented, the mechanisms by which the H5N1 viruses cause fatal disease remain unclear. In the present study, we demonstrate that human pulmonary microvascular endothelial cells (hPMEC) had a clearly higher susceptibility to infection by H5N1 HPAIV than to infection by human influenza viruses. This was measurable by de novo intracellular nucleoprotein production and virus replication. It was also related to a relatively higher binding capacity to cellular receptors. After infection of hPMEC, cell activation markers E-selectin and P-selectin were upregulated, and the proinflammatory cytokines interleukin-6 and beta interferon were secreted. H5N1 virus infection was also associated with an elevated rate of cell death. Reverse genetics analyses demonstrated a major role for the viral hemagglutinin in this cell tropism. Overall, avian H5N1 viruses have a particular receptor specificity targeting endothelial cells that is different from human influenza viruses, and this H5N1 receptor specificity could contribute to disease pathogenesis.

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Differences Between Influenza Virus Receptors on Target Cells of Duck and Chicken and Receptor Specificity of the 1997 H5N1 Chicken and Human Influenza Viruses from Hong Kong

Avian Diseases ◽

10.1637/0005-2086-47.s3.1154 ◽

2003 ◽

Vol 47 (s3) ◽

pp. 1154-1160 ◽

Cited By ~ 32

Author(s):

A. S. Gambaryan ◽

A. B. Tuzikov ◽

N. V. Bovin ◽

S. S. Yamnikova ◽

D. K. Lvov ◽

...

Keyword(s):

Influenza Virus ◽

Hong Kong ◽

Influenza Viruses ◽

Target Cells ◽

Human Influenza ◽

Receptor Specificity ◽

Virus Receptors

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Enhanced Human-Type Receptor Binding by Ferret-Transmissible H5N1 with a K193T Mutation

Journal of Virology ◽

10.1128/jvi.02016-17 ◽

2018 ◽

Vol 92 (10) ◽

Cited By ~ 8

Author(s):

Wenjie Peng ◽

Kim M. Bouwman ◽

Ryan McBride ◽

Oliver C. Grant ◽

Robert J. Woods ◽

...

Keyword(s):

Receptor Binding ◽

Influenza Virus Infection ◽

Binding Pocket ◽

Influenza Viruses ◽

Human Model ◽

Human Influenza ◽

Emerging Viruses ◽

Receptor Specificity ◽

Human Type ◽

Type Receptor

ABSTRACT All human influenza pandemics have originated from avian influenza viruses. Although multiple changes are needed for an avian virus to be able to transmit between humans, binding to human-type receptors is essential. Several research groups have reported mutations in H5N1 viruses that exhibit specificity for human-type receptors and promote respiratory droplet transmission between ferrets. Upon detailed analysis, we have found that these mutants exhibit significant differences in fine receptor specificity compared to human H1N1 and H3N2 and retain avian-type receptor binding. We have recently shown that human influenza viruses preferentially bind to α2-6-sialylated branched N-linked glycans, where the sialic acids on each branch can bind to receptor sites on two protomers of the same hemagglutinin (HA) trimer. In this binding mode, the glycan projects over the 190 helix at the top of the receptor-binding pocket, which in H5N1 would create a stearic clash with lysine at position 193. Thus, we hypothesized that a K193T mutation would improve binding to branched N-linked receptors. Indeed, the addition of the K193T mutation to the H5 HA of a respiratory-droplet-transmissible virus dramatically improves both binding to human trachea epithelial cells and specificity for extended α2-6-sialylated N-linked glycans recognized by human influenza viruses. IMPORTANCE Infections by avian H5N1 viruses are associated with a high mortality rate in several species, including humans. Fortunately, H5N1 viruses do not transmit between humans because they do not bind to human-type receptors. In 2012, three seminal papers have shown how these viruses can be engineered to transmit between ferrets, the human model for influenza virus infection. Receptor binding, among others, was changed, and the viruses now bind to human-type receptors. Receptor specificity was still markedly different compared to that of human influenza viruses. Here we report an additional mutation in ferret-transmissible H5N1 that increases human-type receptor binding. K193T seems to be a common receptor specificity determinant, as it increases human-type receptor binding in multiple subtypes. The K193T mutation can now be used as a marker during surveillance of emerging viruses to assess potential pandemic risk.

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The susceptibility of circulating human influenza viruses to tizoxanide, the active metabolite of nitazoxanide

Antiviral Research ◽

10.1016/j.antiviral.2017.10.002 ◽

2017 ◽

Vol 147 ◽

pp. 142-148 ◽

Cited By ~ 26

Author(s):

Danielle Tilmanis ◽

Carel van Baalen ◽

Ding Yuan Oh ◽

Jean-Francois Rossignol ◽

Aeron C. Hurt

Keyword(s):

Active Metabolite ◽

Influenza Viruses ◽

Human Influenza

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Genetic evolution of the neuraminidase of influenza A (H3N2) viruses from 1968 to 2009 and its correspondence to haemagglutinin evolution

Journal of General Virology ◽

10.1099/vir.0.043059-0 ◽

2012 ◽

Vol 93 (9) ◽

pp. 1996-2007 ◽

Cited By ~ 35

Author(s):

Kim B. Westgeest ◽

Miranda de Graaf ◽

Mathieu Fourment ◽

Theo M. Bestebroer ◽

Ruud van Beek ◽

...

Keyword(s):

Humoral Immunity ◽

Influenza A ◽

Phylogenetic Trees ◽

Influenza Viruses ◽

Genetic Maps ◽

Genetic Evolution ◽

Human Influenza ◽

Nucleotide Level ◽

Antigenic Evolution ◽

Positively Selected Sites

Each year, influenza viruses cause epidemics by evading pre-existing humoral immunity through mutations in the major glycoproteins: the haemagglutinin (HA) and the neuraminidase (NA). In 2004, the antigenic evolution of HA of human influenza A (H3N2) viruses was mapped (Smith et al., Science 305, 371–376, 2004) from its introduction in humans in 1968 until 2003. The current study focused on the genetic evolution of NA and compared it with HA using the dataset of Smith and colleagues, updated to the epidemic of the 2009/2010 season. Phylogenetic trees and genetic maps were constructed to visualize the genetic evolution of NA and HA. The results revealed multiple reassortment events over the years. Overall rates of evolutionary change were lower for NA than for HA1 at the nucleotide level. Selection pressures were estimated, revealing an abundance of negatively selected sites and sparse positively selected sites. The differences found between the evolution of NA and HA1 warrant further analysis of the evolution of NA at the phenotypic level, as has been done previously for HA.

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Positive Selection in CD8+T-Cell Epitopes of Influenza Virus Nucleoprotein Revealed by a Comparative Analysis of Human and Swine Viral Lineages

Journal of Virology ◽

10.1128/jvi.01571-15 ◽

2015 ◽

Vol 89 (22) ◽

pp. 11275-11283 ◽

Cited By ~ 27

Author(s):

Heather M. Machkovech ◽

Trevor Bedford ◽

Marc A. Suchard ◽

Jesse D. Bloom

Keyword(s):

T Cells ◽

Influenza Virus ◽

T Cell ◽

Positive Selection ◽

Swine Influenza ◽

Selective Advantage ◽

Influenza Viruses ◽

T Cell Epitopes ◽

Human Influenza ◽

Human Influenza Virus

ABSTRACTNumerous experimental studies have demonstrated that CD8+T cells contribute to immunity against influenza by limiting viral replication. It is therefore surprising that rigorous statistical tests have failed to find evidence of positive selection in the epitopes targeted by CD8+T cells. Here we use a novel computational approach to test for selection in CD8+T-cell epitopes. We define all epitopes in the nucleoprotein (NP) and matrix protein (M1) with experimentally identified human CD8+T-cell responses and then compare the evolution of these epitopes in parallel lineages of human and swine influenza viruses that have been diverging since roughly 1918. We find a significant enrichment of substitutions that alter human CD8+T-cell epitopes in NP of human versus swine influenza virus, consistent with the idea that these epitopes are under positive selection. Furthermore, we show that epitope-altering substitutions in human influenza virus NP are enriched on the trunk versus the branches of the phylogenetic tree, indicating that viruses that acquire these mutations have a selective advantage. However, even in human influenza virus NP, sites in T-cell epitopes evolve more slowly than do nonepitope sites, presumably because these epitopes are under stronger inherent functional constraint. Overall, our work demonstrates that there is clear selection from CD8+T cells in human influenza virus NP and illustrates how comparative analyses of viral lineages from different hosts can identify positive selection that is otherwise obscured by strong functional constraint.IMPORTANCEThere is a strong interest in correlates of anti-influenza immunity that are protective against diverse virus strains. CD8+T cells provide such broad immunity, since they target conserved viral proteins. An important question is whether T-cell immunity is sufficiently strong to drive influenza virus evolution. Although many studies have shown that T cells limit viral replication in animal models and are associated with decreased symptoms in humans, no studies have proven with statistical significance that influenza virus evolves under positive selection to escape T cells. Here we use comparisons of human and swine influenza viruses to rigorously demonstrate that human influenza virus evolves under pressure to fix mutations in the nucleoprotein that promote escape from T cells. We further show that viruses with these mutations have a selective advantage since they are preferentially located on the “trunk” of the phylogenetic tree. Overall, our results show that CD8+T cells targeting nucleoprotein play an important role in shaping influenza virus evolution.

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N-Glycolylneuraminic Acid in Animal Models for Human Influenza A Virus

Viruses ◽

10.3390/v13050815 ◽

2021 ◽

Vol 13 (5) ◽

pp. 815

Author(s):

Cindy M. Spruit ◽

Nikoloz Nemanichvili ◽

Masatoshi Okamatsu ◽

Hiromu Takematsu ◽

Geert-Jan Boons ◽

...

Keyword(s):

Sialic Acid ◽

Animal Models ◽

Influenza A ◽

Influenza Virus Infection ◽

Influenza Viruses ◽

Upper Respiratory Tract ◽

Human Influenza ◽

Influenza A Viruses ◽

Sialic Acid Content ◽

Acetylneuraminic Acid

The first step in influenza virus infection is the binding of hemagglutinin to sialic acid-containing glycans present on the cell surface. Over 50 different sialic acid modifications are known, of which N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) are the two main species. Animal models with α2,6 linked Neu5Ac in the upper respiratory tract, similar to humans, are preferred to enable and mimic infection with unadapted human influenza A viruses. Animal models that are currently most often used to study human influenza are mice and ferrets. Additionally, guinea pigs, cotton rats, Syrian hamsters, tree shrews, domestic swine, and non-human primates (macaques and marmosets) are discussed. The presence of NeuGc and the distribution of sialic acid linkages in the most commonly used models is summarized and experimentally determined. We also evaluated the role of Neu5Gc in infection using Neu5Gc binding viruses and cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH)-/- knockout mice, which lack Neu5Gc and concluded that Neu5Gc is unlikely to be a decoy receptor. This article provides a base for choosing an appropriate animal model. Although mice are one of the most favored models, they are hardly naturally susceptible to infection with human influenza viruses, possibly because they express mainly α2,3 linked sialic acids with both Neu5Ac and Neu5Gc modifications. We suggest using ferrets, which resemble humans closely in the sialic acid content, both in the linkages and the lack of Neu5Gc, lung organization, susceptibility, and disease pathogenesis.

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Improving pandemic influenza risk assessment

eLife ◽

10.7554/elife.03883 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 43

Author(s):

Colin A Russell ◽

Peter M Kasson ◽

Ruben O Donis ◽

Steven Riley ◽

John Dunbar ◽

...

Keyword(s):

Risk Assessment ◽

Pandemic Influenza ◽

Influenza A ◽

Sequence Data ◽

Virus Genome ◽

Influenza Viruses ◽

Influenza Surveillance ◽

Human Influenza ◽

Influenza A Viruses ◽

Virus Genotype

Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal in public health research. As influenza virus genome sequencing becomes cheaper, faster, and more readily available, the ability to predict pandemic potential from sequence data could transform pandemic influenza risk assessment capabilities. However, the complexities of the relationships between virus genotype and phenotype make such predictions extremely difficult. The integration of experimental work, computational tool development, and analysis of evolutionary pathways, together with refinements to influenza surveillance, has the potential to transform our ability to assess the risks posed to humans by non-human influenza viruses and lead to improved pandemic preparedness and response.

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