UBIQUITOUS REASSORTMENTS IN INFLUENZA A VIRUSES

The influenza A virus is a negative-stranded RNA virus composed of eight segmented RNA molecules, including polymerases (PB2, PB1, PA), hemagglutinin (HA), nucleoprotein (NP), neuraminidase (NA), matrix protein (MP), and nonstructure gene (NS). The influenza A viruses are notorious for rapid mutations, frequent reassortments, and possible recombinations. Among these evolutionary events, reassortments refer to exchanges of discrete RNA segments between co-infected influenza viruses, and they have facilitated the generation of pandemic and epidemic strains. Thus, identification of reassortments will be critical for pandemic and epidemic prevention and control. This paper presents a reassortment identification method based on distance measurement using complete composition vector (CCV) and segment clustering using a minimum spanning tree (MST) algorithm. By applying this method, we identified 34 potential reassortment clusters among 2,641 PB2 segments of influenza A viruses. Among the 83 serotypes tested, at least 56 (67.46%) exchanged their fragments with another serotype of influenza A viruses. These identified reassortments involve 1,957 H2N1 and 1,968 H3N2 influenza pandemic strains as well as H5N1 avian influenza virus isolates, which have generated the potential for a future pandemic threat. More frequent reassortments were found to occur in wild birds, especially migratory birds. This MST clustering program is written in Java and will be available upon request.

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Evidence for history-dependence of influenza pandemic emergence

Scientific Reports ◽

10.1038/srep43623 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 2

Author(s):

Edward M. Hill ◽

Michael J. Tildesley ◽

Thomas House

Keyword(s):

Influenza A ◽

Influenza Pandemic ◽

Influenza A Viruses ◽

History Dependence ◽

Influenza Pandemics ◽

Gamma Distributions ◽

Time Periods ◽

Pandemic Strains ◽

Modelling Assumptions ◽

High Level

Abstract Influenza A viruses have caused a number of global pandemics, with considerable mortality in humans. Here, we analyse the time periods between influenza pandemics since 1700 under different assumptions to determine whether the emergence of new pandemic strains is a memoryless or history-dependent process. Bayesian model selection between exponential and gamma distributions for these time periods gives support to the hypothesis of history-dependence under eight out of nine sets of modelling assumptions. Using the fitted parameters to make predictions shows a high level of variability in the modelled number of pandemics from 2010–2110. The approach we take here relies on limited data, so is uncertain, but it provides cheap, safe and direct evidence relating to pandemic emergence, a field where indirect measurements are often made at great risk and cost.

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Wild Birds in Live Birds Markets: Potential Reservoirs of Enzootic Avian Influenza Viruses and Antimicrobial Resistant Enterobacteriaceae in Northern Egypt

Pathogens ◽

10.3390/pathogens9030196 ◽

2020 ◽

Vol 9 (3) ◽

pp. 196 ◽

Cited By ~ 2

Author(s):

Nehal M. Nabil ◽

Ahmed M. Erfan ◽

Maram M. Tawakol ◽

Naglaa M. Haggag ◽

Mahmoud M. Naguib ◽

...

Keyword(s):

Influenza A ◽

Migratory Birds ◽

Wild Birds ◽

Influenza Viruses ◽

Northern Coast ◽

Influenza A Viruses ◽

E Coli ◽

Ha Gene ◽

Live Bird

Wild migratory birds are often implicated in the introduction, maintenance, and global dissemination of different pathogens, such as influenza A viruses (IAV) and antimicrobial-resistant (AMR) bacteria. Trapping of migratory birds during their resting periods at the northern coast of Egypt is a common and ancient practice performed mainly for selling in live bird markets (LBM). In the present study, samples were collected from 148 wild birds, representing 14 species, which were being offered for sale in LBM. All birds were tested for the presence of AIV and enterobacteriaceae. Ten samples collected from Northern Shoveler birds (Spatula clypeata) were positive for IAV and PCR sub-typing and pan HA/NA sequencing assays detected H5N8, H9N2, and H6N2 viruses in four, four, and one birds, respectively. Sequencing of the full haemagglutinin (HA) gene revealed a high similarity with currently circulating IAV in Egypt. From all the birds, E. coli was recovered from 37.2% and Salmonella from 20.2%, with 66–96% and 23–43% isolates being resistant to at least one of seven selected critically important antimicrobials (CIA), respectively. The presence of enzootic IAV and the wide prevalence of AMR enterobacteriaceae in wild birds highlight the potential role of LBM in the spread of different pathogens from and to wild birds. Continued surveillance of both AIV and antimicrobial-resistant enterobacteriaceae in wild birds’ habitats is urgently needed.

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Evolution and Molecular Epidemiology of H9N2 Influenza A Viruses from Quail in Southern China, 2000 to 2005

Journal of Virology ◽

10.1128/jvi.02316-06 ◽

2006 ◽

Vol 81 (6) ◽

pp. 2635-2645 ◽

Cited By ~ 128

Author(s):

K. M. Xu ◽

K. S. Li ◽

G. J. D. Smith ◽

J. W. Li ◽

H. Tai ◽

...

Keyword(s):

Influenza Virus ◽

Influenza A ◽

Southern China ◽

Phylogenetic Analyses ◽

Influenza Viruses ◽

Influenza A Viruses ◽

Laboratory Findings ◽

Virus Surveillance ◽

Important Host ◽

Pandemic Strains

ABSTRACT H9N2 influenza viruses have become established and maintain long-term endemicity in terrestrial poultry in Asian countries. Occasionally these viruses transmit to other mammals, including humans. Increasing epidemiological and laboratory findings suggest that quail may be an important host, as they are susceptible to different subtypes of influenza viruses. To better understand the role of quail in influenza virus ecology and evolution, H9N2 viruses isolated from quail during 2000 to 2005 were antigenically and genetically characterized. Our results showed that H9N2 viruses are prevalent year-round in southern China and replicate mainly asymptomatically in the respiratory tract of quail. Genetic analysis revealed that both the G1-like and Ck/Bei-like H9N2 lineages were cocirculating in quail since 2000. Phylogenetic analyses demonstrated that most of the isolates tested were double- or multiple-reassortant variants, with four G1-like and 16 Ck/Bei-like genotypes recognized. A novel genotype of G1-like virus became predominant in quail since 2003, while multiple Ck/Bei-like genotypes were introduced into quail, wherein they incorporated G1-like gene segments, but none of them became established in this host. Those Ck/Bei-like reassortants generated in quail have then been introduced into other poultry. These complex interactions form a two-way transmission system between quail and other types of poultry. The present study provides evidence that H9N2 and H5N1 subtype viruses have also exchanged gene segments to generate currently circulating reassortants of both subtypes that have pandemic potential. Continuing influenza virus surveillance in poultry is critical to understanding the genesis and emergence of potentially pandemic strains in this region.

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A Non-phylogeny-dependent Reassortment Detection Method for Influenza A Viruses

Frontiers in Virology ◽

10.3389/fviro.2021.751196 ◽

2021 ◽

Vol 1 ◽

Author(s):

Xingfei Gong ◽

Mingda Hu ◽

Boqian Wang ◽

Haoyi Yang ◽

Yuan Jin ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Detection Method ◽

Rna Virus ◽

Self Organizing Map ◽

Influenza A Viruses ◽

Multiple Sequence ◽

Distance Methods ◽

Virus Reassortment ◽

Pandemic Strains

Influenza A virus is a segmented RNA virus whose genome consists of 8 single-stranded negative-sense RNA segments. This unique genetic structure allows viruses to exchange their segments through reassortment when they infect the same host cell. Studying the determination and nature of influenza A virus reassortment is critical to understanding the generation of pandemic strains and the spread of viruses across species. Reassortment detection is the first step in influenza A virus reassortment research. Several methods for automatic detection of reassortment have been proposed, which can be roughly divided into two categories: phylogenetic methods and distance methods. In this article, we proposed a reassortment detection method that does not require multiple sequence alignment and phylogenetic analysis. We extracted the codon features from the segment sequence and expressed the sequence as a feature vector, and then used the clustering method of self-organizing map to cluster the sequence for each segment. Based on the clustering results and the epidemiological information of the virus, the reassortment detection was implemented. We used this method to perform reassortment detection on the collected 7,075 strains from Asia and identified 516 reassortment events. We also conducted a statistical analysis of the identified reassortment events and found conclusions consistent with previous studies. Our method will provide new insights for automating reassortment detection tasks and understanding the reassortment patterns of influenza A viruses.

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Repositioning Drugs on Human Influenza A Viruses Based on a Novel Nuclear Norm Minimization Method

Frontiers in Physiology ◽

10.3389/fphys.2020.597494 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hang Liang ◽

Li Zhang ◽

Lina Wang ◽

Man Gao ◽

Xiangfeng Meng ◽

...

Keyword(s):

Influenza A ◽

Chemical Structure ◽

Cross Validation ◽

Drug Repositioning ◽

Influenza Pandemic ◽

Protein Docking ◽

Influenza Viruses ◽

Antigenic Drift ◽

Nuclear Norm ◽

Influenza A Viruses

Influenza A viruses, especially H3N2 and H1N1 subtypes, are viruses that often spread among humans and cause influenza pandemic. There have been several big influenza pandemics that have caused millions of human deaths in history, and the threat of influenza viruses to public health is still serious nowadays due to the frequent antigenic drift and antigenic shift events. However, only few effective anti-flu drugs have been developed to date. The high development cost, long research and development time, and drug side effects are the major bottlenecks, which could be relieved by drug repositioning. In this study, we proposed a novel antiviral Drug Repositioning method based on minimizing Matrix Nuclear Norm (DRMNN). Specifically, a virus-drug correlation database consisting of 34 viruses and 205 antiviral drugs was first curated from public databases and published literature. Together with drug similarity on chemical structure and virus sequence similarity, we formulated the drug repositioning problem as a low-rank matrix completion problem, which was solved by minimizing the nuclear norm of a matrix with a few regularization terms. DRMNN was compared with three recent association prediction algorithms. The AUC of DRMNN in the global fivefold cross-validation (fivefold CV) is 0.8661, and the AUC in the local leave-one-out cross-validation (LOOCV) is 0.6929. Experiments have shown that DRMNN is better than other algorithms in predicting which drugs are effective against influenza A virus. With H3N2 as an example, 10 drugs most likely to be effective against H3N2 viruses were listed, among which six drugs were reported, in other literature, to have some effect on the viruses. The protein docking experiments between the chemical structure of the prioritized drugs and viral hemagglutinin protein also provided evidence for the potential of the predicted drugs for the treatment of influenza.

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A multiplex real-time PCR assay for detection of oseltamivir-resistant strains of influenza virus

Open Life Sciences ◽

10.2478/s11535-014-0296-z ◽

2014 ◽

Vol 9 (6) ◽

pp. 628-633

Author(s):

Dawid Nidzworski ◽

Joanna Dobkowska ◽

Marcin Hołysz ◽

Beata Gromadzka ◽

Bogusław Szewczyk

Keyword(s):

Real Time ◽

Influenza A Virus ◽

Real Time Pcr ◽

Influenza A ◽

Influenza Pandemic ◽

Neuraminidase Inhibitor ◽

Influenza Viruses ◽

Antigenic Drift ◽

Influenza A Viruses ◽

Oseltamivir Resistance

AbstractInfluenza is a contagious disease of humans and animals caused by viruses belonging to the Orthomyxoviridae family. The influenza A virus genome consists of negative sense, single-stranded, segmented RNA. Influenza viruses are classified into subtypes based on two surface antigens known as hemagglutinin (H) and neuraminidase (N). The main problem with influenza A viruses infecting humans is drug resistance, which is caused by antigenic changes. A few antiviral drugs are available, but the most popular is the neuraminidase inhibitor — oseltamivir. The resistance against this drug has probably developed through antigenic drift by a point mutation in one amino acid at position 275 (H275Y). In order to prevent a possible influenza pandemic it is necessary to develop fast diagnostic tests. The aim of this project was to develop a new test for detection of influenza A virus and determination of oseltamivir resistance/sensitivity in humans. Detection and differentiation of oseltamivir resistance/sensitivity of influenza A virus was based on real-time PCR. This test contains two TaqMan probes, which work at different wavelengths. Application of techniques like multiplex real-time PCR has greatly enhanced the capability for surveillance and characterization of influenza viruses. After its potential validation, this test can be used for diagnosis before treatment.

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Oseltamivir susceptibility in south-western France during the 2007-8 and 2008-9 influenza epidemics and the ongoing influenza pandemic 2009

Eurosurveillance ◽

10.2807/ese.14.38.19334-en ◽

2009 ◽

Vol 14 (38) ◽

Cited By ~ 4

Author(s):

S Burrel ◽

L Roncin ◽

M E Lafon ◽

H Fleury

Keyword(s):

Influenza A ◽

Seasonal Influenza ◽

Influenza Pandemic ◽

Influenza Viruses ◽

Neuraminidase Inhibitors ◽

Influenza A Viruses ◽

Oseltamivir Resistance ◽

The Past ◽

Influenza A H1n1 ◽

Recent Emergence

The recent emergence of seasonal influenza A(H1N1) strains resistant to oseltamivir makes it necessary to monitoring carefully the susceptibility of human influenza viruses to neuraminidase inhibitors. We report the prevalence of the oseltamivir resistance among influenza A viruses circulating in south-western France over the past three years: seasonal influenza A(H1N1), seasonal influenza A(H3N2), and the influenza A(H1N1)v viruses associated with the ongoing 2009 pandemic. The main result of the study is the absence of oseltamivir resistance in the pandemic H1N1 strains studied so far (n=129).

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Hemagglutinin Compatibility between Avian and Human Influenza A viruses using Human Matrix Protein: Based on Scholtissek et al.’s (2002) Article

Journal of Student Science and Technology ◽

10.13034/jsst.v8i2.72 ◽

2015 ◽

Vol 8 (2) ◽

Author(s):

Katherine Lien

Keyword(s):

Experimental Model ◽

Influenza A ◽

Matrix Protein ◽

Influenza Viruses ◽

M Protein ◽

Human Influenza ◽

Influenza A Viruses ◽

Large Segment ◽

A Cell ◽

Different Strains

Through the review of Scholtissek et al.(1), evolution between different strains of influenza A viruses were examined to enable better preparation for future pandemics. Pandemics are the result of antigenic shifts, cumulative reassortants between circulating viruses that form novel gene sequences. The process may produce a virus which a large segment of the population has no immunological memory of, and consequently, are susceptible to the strain.The pandemics in 1918, 1967, 1968 and 2009 were caused by influenza A viruses with hemagglutinin (HA) proteins of 1, 2, or 3 - three out of sixteen known HA subtypes. This raises the question whether pandemics can contain other HA subtypes. Since influenza viruses have segmented genomes, it may require at least two different strains to swap their gene segments in order to co-infect a cell; the better viral compatibility between the parent viruses, the more virulent the reassortant is. A collection of HA subtypes in avian strains and Matrix (M) protein in human strains were used in the experimental model by Scholtissek et al. to examine the recombinants’ survivability and virulence. Although the results conclude that it is not possible for future pandemics to contain other HA subtypes, the work of Scholtissek et al. leads to further research on influenza A reservoirs. Ce document est un résumé au sujet de l'article de Christoph Scholtissek (1) publié en 2002. J’examinerai son modèle expérimental, en mettant en évidence les résultats et donnant un aperçu des recherches plus élaborées. En étudiant des modèles de la coopération entre les virus, ceci permet d’aider à se préparer face aux futures pandémies et épidémies. De tels évènements sont causés par des changements antigéniques produits par l’accumulation de réassortiments entre les virus en circulation et divers éléments. Les virus grippaux A sont en constante évolution, et nécessitent une surveillance constante en anticipation à une pandémie. Les pandémies antérieures, soient celles en 1918, 1957, 1968 et 2009, ont démontré à avoir les hémagglutinines (HA) 1, 2 et 3 – trois des seize sous-types HA possibles. Ceci remet en question la possibilité que les pandémies puissent contenir d’autres sous-types HA. Afin que les virus puissent former des virus réassortis potentiellement nouveaux ils doivent bien coopérer, ce qui est précisément ce que Scholtissek tente d'enquêter. Son modèle expérimental implique des réassortiments entre les différents sous-types d’HA dans des souches aviaires et des souches humaines détenant des M-protéines, afin de déterminer la compatibilité virale. Bien que les résultats concluent qu'il est très peu probable que de futures pandémies détiennent d'autres sous-types HA, ils fournissent des indices du potentiel pandémique. En outre, son article incite la recherche plus à fond sur d’autres réservoirs de la grippe A, les méthodes pour surmonter les barrières entre espèces et le réassortiment efficaces.

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Virus-Like Particles Containing the Tetrameric Ectodomain of Influenza Matrix Protein 2 and Flagellin Induce Heterosubtypic Protection in Mice

BioMed Research International ◽

10.1155/2013/686549 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 8

Author(s):

Li Wang ◽

Ying-Chun Wang ◽

Hao Feng ◽

Tamanna Ahmed ◽

Richard W. Compans ◽

...

Keyword(s):

Influenza A ◽

Matrix Protein ◽

Influenza Virus Infection ◽

Influenza Viruses ◽

Influenza A Viruses ◽

Lethal Challenge ◽

Virus Like Particles ◽

Chimeric Vlps ◽

Mucosal Antibody ◽

Cellular Immune

The ectodomain of matrix protein 2 (M2e) is highly conserved among influenza A viruses and can be a promising candidate antigen for a broadly cross-protective vaccine. In this study, a tetrameric M2e (tM2e) and a truncated form of flagellin (tFliC) were coincorporated into virus-like particles (VLPs) to enhance its immunogenicity. Our data showed that the majority of M2e in VLPs was presented as tetramers by introducing a foreign tetramerization motif GCN4. Intranasal immunization with tM2e VLPs significantly enhanced the levels of serum IgG and IgG subclasses compared to soluble M2e (sM2e) in mice. tM2e VLPs also induced higher M2e-specific T-cell and mucosal antibody responses, conferring complete protection against homologous influenza virus infection. The immunogenicity of tM2e VLPs was further enhanced by coincorporation of the membrane-anchored tFliC (tM2e chimeric VLPs) or coadministration with tFliC VLPs as a mixture, but not the soluble flagellin, inducing strong humoral and cellular immune responses conferring cross-protection against lethal challenge with heterotypic influenza viruses. These results support the development of tM2e chimeric VLPs as universal vaccines and warrant further investigation.

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Alterations of membrane curvature during influenza virus budding

Biochemical Society Transactions ◽

10.1042/bst20140136 ◽

2014 ◽

Vol 42 (5) ◽

pp. 1425-1428 ◽

Cited By ~ 8

Author(s):

Agnieszka Martyna ◽

Jeremy Rossman

Keyword(s):

Lipid Raft ◽

Influenza A ◽

Matrix Protein ◽

Membrane Curvature ◽

Influenza Viruses ◽

Apical Plasma Membrane ◽

Lipid Phase ◽

Influenza A Viruses ◽

Enveloped Virus ◽

Virion Release

Influenza A virus belongs to the Orthomyxoviridae family. It is an enveloped virus that contains a segmented and negative-sense RNA genome. Influenza A viruses cause annual epidemics and occasional major pandemics, are a major cause of morbidity and mortality worldwide, and have a significant financial impact on society. Assembly and budding of new viral particles are a complex and multi-step process involving several host and viral factors. Influenza viruses use lipid raft domains in the apical plasma membrane of polarized epithelial cells as sites of budding. Two viral glycoproteins, haemagglutinin and neuraminidase, concentrate in lipid rafts, causing alterations in membrane curvature and initiation of the budding process. Matrix protein 1 (M1), which forms the inner structure of the virion, is then recruited to the site followed by incorporation of the viral ribonucleoproteins and matrix protein 2 (M2). M1 can alter membrane curvature and progress budding, whereas lipid raft-associated M2 stabilizes the site of budding, allowing for proper assembly of the virion. In the later stages of budding, M2 is localized to the neck of the budding virion at the lipid phase boundary, where it causes negative membrane curvature, leading to scission and virion release.

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