scholarly journals Mucin-mimetic glycan arrays integrating machine learning for analyzing receptor pattern recognition by influenza A viruses

2021 ◽  
Author(s):  
Taryn M. Lucas ◽  
Chitrak Gupta ◽  
Meghan O. Altman ◽  
Emi Sanchez ◽  
Matthew R. Naticchia ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Mammalian Cells ◽  
Influenza A ◽  
Learning Algorithm ◽  
Sialic Acids ◽  
Soluble Form ◽  
Support Vector ◽  
Glycan Array ◽  
Influenza A Viruses ◽  
New Host

ABSTRACTInfluenza A viruses (IAVs) exploit host glycans in airway epithelial mucosa to gain entry and initiate infection. Rapid detection of changes in IAV specificity towards host glycan classes can provide early indication of virus transmissibility and infection potential. IAVs use hemagglutinins (HA) to bind sialic acids linked to larger glycan structures and a switch in HA specificity from α2,3-to α2,6-linked sialoglycans is considered a prerequisite for viral transmission from birds to humans. While the changes in HA structure associated with the evolution of binding phenotype have been mapped, the influence of glycan receptor presentation on IAV specificity remains obscured. Here, we describe a glycan array platform which uses synthetic mimetics of mucin glycoproteins to model how receptor presentation in the mucinous glycocalyx, including glycan type and valency of the glycoconjugates and their surface density, impact IAV binding. We found that H1N1 virus produced in embryonated chicken eggs, which recognizes both receptor types, exclusively engaged mucin-mimetics carrying α2,3-linked sialic acids in their soluble form. The virus was able utilize both receptor structures when the probes were immobilized on the array; however, increasing density in the mucin-mimetic brush diminished viral adhesion. Propagation in mammalian cells produced a change in receptor pattern recognition by the virus, without altering its HA affinity, toward improved binding of α2,6-sialylated mucin mimetics and reduced sensitivity to surface crowding of the probes. Application of a support vector machine (SVM) learning algorithm as part of the glycan array binding analysis efficiently characterized this shift in binding preference and may prove useful to study the evolution of viral responses to a new host.

scholarly journals Plasticity of the Influenza Virus H5 HA Protein

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huihui Kong ◽  
David F. Burke ◽  
Tiago Jose da Silva Lopes ◽  
Kosuke Takada ◽  
Masaki Imai ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Amino Acid ◽  
Mammalian Cells ◽  
Influenza A ◽  
Viral Antigen ◽  
Influenza Viruses ◽  
Influenza A Viruses ◽  
Highly Pathogenic ◽  
Antigenic Properties ◽  
Ha Protein

ABSTRACT Since the emergence of highly pathogenic avian influenza viruses of the H5 subtype, the major viral antigen, hemagglutinin (HA), has undergone constant evolution, resulting in numerous genetic and antigenic (sub)clades. To explore the consequences of amino acid changes at sites that may affect the antigenicity of H5 viruses, we simultaneously mutated 17 amino acid positions of an H5 HA by using a synthetic gene library that, theoretically, encodes all combinations of the 20 amino acids at the 17 positions. All 251 mutant viruses sequenced possessed ≥13 amino acid substitutions in HA, demonstrating that the targeted sites can accommodate a substantial number of mutations. Selection with ferret sera raised against H5 viruses of different clades resulted in the isolation of 39 genotypes. Further analysis of seven variants demonstrated that they were antigenically different from the parental virus and replicated efficiently in mammalian cells. Our data demonstrate the substantial plasticity of the influenza virus H5 HA protein, which may lead to novel antigenic variants. IMPORTANCE The HA protein of influenza A viruses is the major viral antigen. In this study, we simultaneously introduced mutations at 17 amino acid positions of an H5 HA expected to affect antigenicity. Viruses with ≥13 amino acid changes in HA were viable, and some had altered antigenic properties. H5 HA can therefore accommodate many mutations in regions that affect antigenicity. The substantial plasticity of H5 HA may facilitate the emergence of novel antigenic variants.

scholarly journals Characterization of Subtype H6 Avian Influenza A Viruses Isolated From Wild Birds in Poyang Lake, China

2021 ◽  
Vol 8 ◽  
Author(s):  
Zhimin Wan ◽  
Qiuqi Kan ◽  
Zhehong Zhao ◽  
Hongxia Shao ◽  
Thomas J. Deliberto ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Avian Influenza ◽  
Mammalian Cells ◽  
Influenza A ◽  
Poyang Lake ◽  
Wild Birds ◽  
Mouse Lung ◽  
Influenza A Viruses ◽  
Domestic Poultry ◽  
History Of

Subtype H6 avian influenza A viruses (IAVs) are enzootic and genetically diverse in both domestic poultry and wild waterfowl and may cause spillovers in both pigs and humans. Thus, it is important to understand the genetic diversity of H6 IAVs in birds and their zoonotic potential. Compared with that in domestic poultry, the genetic diversity of H6 viruses in wild birds in China has not been well-understood. In this study, five H6 viruses were isolated from wild birds in Poyang Lake, China, and genetic analyses showed that these isolates are clustered into four genotypes associated with reassortments among avian IAVs from domestic poultry and wild birds in China and those from Eurasia and North America and that these viruses exhibited distinct phenotypes in growth kinetics analyses with avian and mammalian cells lines and in mouse challenge experiments. Of interest is that two H6 isolates from the Eurasian teal replicated effectively in the mouse lung without prior adaptation, whereas the other three did not. Our study suggested that there are variations in the mammalian viral replication efficiency phenotypic among genetically diverse H6 IAVs in wild birds and that both intra- and inter-continental movements of IAVs through wild bird migration may facilitate the emergence of novel H6 IAV reassortants with the potential for replicating in mammals, including humans. Continued surveillance to monitor the diversity of H6 IAVs in wild birds is necessary to increase our understanding of the natural history of IAVs.

scholarly journals PB2 Residue 271 Plays a Key Role in Enhanced Polymerase Activity of Influenza A Viruses in Mammalian Host Cells

2010 ◽  
Vol 84 (9) ◽  
pp. 4395-4406 ◽  
Author(s):  
Kendra A. Bussey ◽  
Tatiana L. Bousse ◽  
Emily A. Desmet ◽  
Baek Kim ◽  
Toru Takimoto
Keyword(s):  
Mammalian Cells ◽  
Influenza A ◽  
Virus Titer ◽  
Polymerase Activity ◽  
Influenza Viruses ◽  
Host Cells ◽  
Mammalian Host ◽  
Influenza A Viruses ◽  
H5n1 Influenza ◽  
Avian Viruses

ABSTRACT The direct infection of humans with highly pathogenic avian H5N1 influenza viruses has suggested viral mutation as one mechanism for the emergence of novel human influenza A viruses. Although the polymerase complex is known to be a key component in host adaptation, mutations that enhance the polymerase activity of avian viruses in mammalian hosts are not fully characterized. The genomic comparison of influenza A virus isolates has identified highly conserved residues in influenza proteins that are specific to either human or avian viruses, including 10 residues in PB2. We characterized the activity of avian polymerase complexes containing avian-to-human mutations at these conserved PB2 residues and found that, in addition to the E627K mutation, the PB2 mutation T271A enhances polymerase activity in human cells. We confirmed the effects of the T271A mutation using recombinant WSN viruses containing avian NP and polymerase genes with wild-type (WT) or mutant PB2. The 271A virus showed enhanced growth compared to that of the WT in mammalian cells in vitro. The 271A mutant did not increase viral pathogenicity significantly in mice compared to that of the 627K mutant, but it did enhance the lung virus titer. Also, cell infiltration was more evident in lungs of 271A-infected mice than in those of the WT. Interestingly, the avian-derived PB2 of the 2009 pandemic H1N1 influenza virus has 271A. The characterization of the polymerase activity of A/California/04/2009 (H1N1) and corresponding PB2 mutants indicates that the high polymerase activity of the pandemic strain in mammalian cells is, in part, dependent on 271A. Our results clearly indicate the contribution of PB2 amino acid 271 to enhanced polymerase activity and viral growth in mammalian hosts.

scholarly journals Evidence for Avian and Human Host Cell Factors That Affect the Activity of Influenza Virus Polymerase

2010 ◽  
Vol 84 (19) ◽  
pp. 9978-9986 ◽  
Author(s):  
Olivier Moncorgé ◽  
Manuela Mura ◽  
Wendy S. Barclay
Keyword(s):  
Influenza Virus ◽  
Avian Influenza ◽  
Avian Influenza Virus ◽  
Host Range ◽  
Influenza A ◽  
Human Cells ◽  
Influenza A Viruses ◽  
New Host ◽  
Range Restriction ◽  
Positive Factor

ABSTRACT Typical avian influenza A viruses do not replicate efficiently in humans. The molecular basis of host range restriction and adaptation of avian influenza A viruses to a new host species is still not completely understood. Genetic determinants of host range adaptation have been found on the polymerase complex (PB1, PB2, and PA) as well as on the nucleoprotein (NP). These four viral proteins constitute the minimal set for transcription and replication of influenza viral RNA. It is widely documented that in human cells, avian-derived influenza A viral polymerase is poorly active, but despite extensive study, the reason for this blockade is not known. We monitored the activity of influenza A viral polymerases in heterokaryons formed between avian (DF1) and human (293T) cells. We have discovered that a positive factor present in avian cells enhances the activity of the avian influenza virus polymerase. We found no evidence for the existence of an inhibitory factor for avian virus polymerase in human cells, and we suggest, instead, that the restriction of avian influenza virus polymerases in human cells is the consequence of the absence or the low expression of a compatible positive cofactor. Finally, our results strongly suggest that the well-known adaptative mutation E627K on viral protein PB2 facilitates the ability of a human positive factor to enhance replication of influenza virus in human cells.

scholarly journals Influence of PB2 host-range determinants on the intranuclear mobility of the influenza A virus polymerase

2011 ◽  
Vol 92 (7) ◽  
pp. 1650-1661 ◽  
Author(s):  
Ágnes Foeglein ◽  
Eva M. Loucaides ◽  
Manuela Mura ◽  
Helen M. Wise ◽  
Wendy S. Barclay ◽  
...  
Keyword(s):  
Host Range ◽  
Mammalian Cells ◽  
Influenza A ◽  
Transcriptional Activity ◽  
Specific Activity ◽  
Inhibitory Effects ◽  
Influenza A Viruses ◽  
Viral Polymerase ◽  
Host Restriction ◽  
Cellular Factors

Avian influenza A viruses often do not propagate efficiently in mammalian cells. The viral polymerase protein PB2 is important for this host restriction, with amino-acid polymorphisms at residue 627 and other positions acting as ‘signatures’ of avian- or human-adapted viruses. Restriction is hypothesized to result from differential interactions (either positive or inhibitory) with unidentified cellular factors. We applied fluorescence recovery after photobleaching (FRAP) to investigate the mobility of the viral polymerase in the cell nucleus using A/PR/8/34 and A/Turkey/England/50-92/91 as model strains. As expected, transcriptional activity of a polymerase with the avian PB2 protein was strongly dependent on the identity of residue 627 in human but not avian cells, and this correlated with significantly slower diffusion of the inactive polymerase in human but not avian nuclei. In contrast, the activity and mobility of the PR8 polymerase was affected much less by residue 627. Sequence comparison followed by mutagenic analyses identified residues at known host-range-specific positions 271, 588 and 701 as well as a novel determinant at position 636 as contributors to host-specific activity of both PR8 and Turkey PB2 proteins. Furthermore, the correlation between poor transcriptional activity and slow diffusional mobility was maintained. However, activity did not obligatorily correlate with predicted surface charge of the 627 domain. Overall, our data support the hypothesis of a host nuclear factor that interacts with the viral polymerase and modulates its activity. While we cannot distinguish between positive and inhibitory effects, the data have implications for how such factors might operate.

Temperature sensitivity on growth and/or replication of H1N1, H1N2 and H3N2 influenza A viruses isolated from pigs and birds in mammalian cells

2010 ◽  
Vol 142 (3-4) ◽  
pp. 232-241 ◽  
Author(s):  
Pascale Massin ◽  
Gaëlle Kuntz-Simon ◽  
Cyril Barbezange ◽  
Céline Deblanc ◽  
Aurélie Oger ◽  
...  
Keyword(s):  
Temperature Sensitivity ◽  
Mammalian Cells ◽  
Influenza A ◽  
Influenza A Viruses ◽  
H3n2 Influenza

scholarly journals Mucin-Mimetic Glycan Arrays Integrating Machine Learning for Analyzing Receptor Pattern Recognition by Influenza a Viruses

2021 ◽  
Author(s):  
Taryn M. Lucas ◽  
Chitrak Gupta ◽  
Meghan O. Altman ◽  
Emi Sanchez ◽  
Matthew R. Naticchia ◽  
...  
Keyword(s):  
Machine Learning ◽  
Pattern Recognition ◽  
Influenza A ◽  
Influenza A Viruses

scholarly journals Aerosol Transmission of Gull-Origin Iceland Subtype H10N7 Influenza A Virus in Ferrets

2019 ◽  
Vol 93 (13) ◽  
Author(s):  
Minhui Guan ◽  
Jeffrey S. Hall ◽  
Xiaojian Zhang ◽  
Robert J. Dusek ◽  
Alicia K. Olivier ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Direct Contact ◽  
Influenza A ◽  
Sialic Acids ◽  
Influenza A Viruses ◽  
Human Interface ◽  
Genomic Analyses ◽  
Avian Origin ◽  
Glycan Receptors ◽  
Human Infections

ABSTRACTSubtype H10 influenza A viruses (IAVs) have been recovered from domestic poultry and various aquatic bird species, and sporadic transmission of these IAVs from avian species to mammals (i.e., human, seal, and mink) are well documented. In 2015, we isolated four H10N7 viruses from gulls in Iceland. Genomic analyses showed four gene segments in the viruses were genetically associated with H10 IAVs that caused influenza outbreaks and deaths among European seals in 2014. Antigenic characterization suggested minimal antigenic variation among these H10N7 isolates and other archived H10 viruses recovered from human, seal, mink, and various avian species in Asia, Europe, and North America. Glycan binding preference analyses suggested that, similar to other avian-origin H10 IAVs, these gull-origin H10N7 IAVs bound to both avian-like alpha 2,3-linked sialic acids and human-like alpha 2,6-linked sialic acids. However, when the gull-origin viruses were compared with another Eurasian avian-origin H10N8 IAV, which caused human infections, the gull-origin virus showed significantly higher binding affinity to human-like glycan receptors. Results from a ferret experiment demonstrated that a gull-origin H10N7 IAV replicated well in turbinate, trachea, and lung, but replication was most efficient in turbinate and trachea. This gull-origin H10N7 virus can be transmitted between ferrets through the direct contact and aerosol routes, without prior adaptation. Gulls share their habitat with other birds and mammals and have frequent contact with humans; therefore, gull-origin H10N7 IAVs could pose a risk to public health. Surveillance and monitoring of these IAVs at the wild bird-human interface should be continued.IMPORTANCESubtype H10 avian influenza A viruses (IAVs) have caused sporadic human infections and enzootic outbreaks among seals. In the fall of 2015, H10N7 viruses were recovered from gulls in Iceland, and genomic analyses showed that the viruses were genetically related with IAVs that caused outbreaks among seals in Europe a year earlier. These gull-origin viruses showed high binding affinity to human-like glycan receptors. Transmission studies in ferrets demonstrated that the gull-origin IAV could infect ferrets, and that the virus could be transmitted between ferrets through direct contact and aerosol droplets. This study demonstrated that avian H10 IAV can infect mammals and be transmitted among them without adaptation. Thus, avian H10 IAV is a candidate for influenza pandemic preparedness and should be monitored in wildlife and at the animal-human interface.

scholarly journals The Critical Interspecies Transmission Barrier at the Animal–Human Interface

2019 ◽  
Vol 4 (2) ◽  
pp. 72 ◽  
Author(s):  
Subbarao
Keyword(s):  
Influenza A ◽  
Influenza Pandemic ◽  
Interspecies Transmission ◽  
Small Subset ◽  
Influenza A Viruses ◽  
Species Barrier ◽  
New Host ◽  
Human Interface ◽  
Wide Range ◽  
Reservoir Hosts

Influenza A viruses (IAVs) infect humans and a wide range of animal species in nature, and waterfowl and shorebirds are their reservoir hosts. Of the 18 haemagglutinin (HA) and 11 neuraminidase (NA) subtypes of IAV, 16 HA and 9 NA subtypes infect aquatic birds. However, among the diverse pool of IAVs in nature, only a limited number of animal IAVs cross the species barrier to infect humans and a small subset of those have spread efficiently from person to person to cause an influenza pandemic. The ability to infect a different species, replicate in the new host and transmit are three distinct steps in this process. Viral and host factors that are critical determinants of the ability of an avian IAV to infect and spread in humans are discussed.

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