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Virology and Bioinformatics from Virology.ca
Virus and bioinformatics articles with some microbiology and immunology thrown in for good measure
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Changes in the hemagglutinin of H5N1 viruses during human infection – Influence on receptor binding

Changes in the hemagglutinin of H5N1 viruses during human infection – Influence on receptor binding | Virology and Bioinformatics from Virology.ca | Scoop.it
Abstract

As avian influenza A(H5N1) viruses continue to circulate in Asia and Africa, global concerns of an imminent pandemic persist. Recent experimental studies suggest that efficient transmission between humans of current H5N1 viruses only requires a few genetic changes. An essential step is alteration of the virus hemagglutinin from preferential binding to avian receptors for the recognition of human receptors present in the upper airway. We have identified receptor-binding changes which emerged during H5N1 infection of humans, due to single amino acid substitutions, Ala134Val and Ile151Phe, in the hemagglutinin. Detailed biological, receptor-binding, and structural analyses revealed reduced binding of the mutated viruses to avian-like receptors, but without commensurate increased binding to the human-like receptors investigated, possibly reflecting a receptor-binding phenotype intermediate in adaptation to more human-like characteristics. These observations emphasize that evolution in nature of avian H5N1 viruses to efficient binding of human receptors is a complex multistep process.

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Mutations associated with severity of the pandemic influenza A(H1N1)pdm09 in humans: a systematic review and meta-analysis of epidemiological evidence - Arch Virol. 2014

Abstract

Mutations in the haemagglutinin (HA), non-structural protein 1 (NS1) and polymerase basic protein 2 (PB2) of influenza viruses have been associated with virulence. This study investigated the association between mutations in these genes in influenza A(H1N1)pdm09 virus and the risk of severe or fatal disease. Searches were conducted on the MEDLINE, EMBASE and Web of Science electronic databases and the reference lists of published studies. The PRISMA and STROBE guidelines were followed in assessing the quality of studies and writing-up. Eighteen (18) studies, from all continents, were included in the systematic review (recruiting patients 0 - 77 years old). The mutation D222G was associated with a significant increase in severe disease (pooled RD: 11 %, 95 % CI: 3.0 % - 18.0 %, p = 0.004) and the risk of fatality (RD: 23 %, 95 % CI: 14.0 %-31.0 %, p = < 0.0001). No association was observed between the mutations HA-D222N, D222E, PB2-E627K and NS1-T123V and severe/fatal disease. The results suggest that no virus quasispecies bearing virulence-conferring mutations in the HA, PB2 and NS1 predominated. However issues of sampling bias, and bias due to uncontrolled confounders such as comorbidities, and viral and bacterial coinfection, should be born in mind. Influenza A viruses should continue to be monitored for the occurrence of virulence-conferring mutations in HA, PB2 and NS1. There are suggestions that respiratory virus coinfections also affect virus virulence. Studies investigating the role of genetic mutations on disease outcome should make efforts to also investigate the role of respiratory virus coinfections.

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Avian Influenza Virus Transmissio... [Curr Top Microbiol Immunol. 2014] - PubMed - NCBI

Avian Influenza Virus Transmissio... [Curr Top Microbiol Immunol. 2014] - PubMed - NCBI | Virology and Bioinformatics from Virology.ca | Scoop.it

Influenza A viruses cause yearly epidemics and occasional pandemics. In addition, zoonotic influenza A viruses sporadically infect humans and may cause severe respiratory disease and fatalities. Fortunately, most of these viruses do not have the ability to be efficiently spread among humans via aerosols or respiratory droplets (airborne transmission) and to subsequently cause a pandemic. However, adaptation of these zoonotic viruses to humans by mutation or reassortment with human influenza A viruses may result in airborne transmissible viruses with pandemic potential. Although our knowledge of factors that affect mammalian adaptation and transmissibility of influenza viruses is still limited, we are beginning to understand some of the biological traits that drive airborne transmission of influenza viruses among mammals. Increased understanding of the determinants and mechanisms of airborne transmission may aid in assessing the risks posed by avian influenza viruses to human health, and preparedness for such risks. This chapter summarizes recent discoveries on the genetic and phenotypic traits required for avian influenza viruses to become airborne transmissible between mammals.

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Scientists Have Developed a Flu Strain Capable of Evading Your Immune System - VICE News

Scientists Have Developed a Flu Strain Capable of Evading Your Immune System - VICE News | Virology and Bioinformatics from Virology.ca | Scoop.it
RT
Scientists Have Developed a Flu Strain Capable of Evading Your Immune System
VICE News
Such "antigenic escape" studies have been performed routinely in virology labs for 30 years.
Clara MacDonald's insight:

Good example of how an article can induce panic in the general public, while the goal of the research is understandable. 

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Spanish Flu's Fatal Timing

Spanish Flu's Fatal Timing | Virology and Bioinformatics from Virology.ca | Scoop.it
The Spanish Flu was likely so lethal because young adults might have had a mismatched immunity to the influenza
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Antiviral strategies against influenza virus: towards new therapeutic approaches - Online First - Springer

Antiviral strategies against influenza virus: towards new therapeutic approaches - Online First - Springer | Virology and Bioinformatics from Virology.ca | Scoop.it

Influenza viruses are major human pathogens responsible for respiratory diseases affecting millions of people worldwide and characterized by high morbidity and significant mortality. Influenza infections can be controlled by vaccination and antiviral drugs. However, vaccines need annual updating and give limited protection. Only two classes of drugs are currently approved for the treatment of influenza: M2 ion channel blockers and neuraminidase inhibitors. However, they are often associated with limited efficacy and adverse side effects. In addition, the currently available drugs suffer from rapid and extensive emergence of drug resistance. All this highlights the urgent need for developing new antiviral strategies with novel mechanisms of action and with reduced drug resistance potential. Several new classes of antiviral agents targeting viral replication mechanisms or cellular proteins/processes are under development. This review gives an overview of novel strategies targeting the virus and/or the host cell for counteracting influenza virus infection.

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H1N-What? Wading Through the Alphabet Soup of Flu Virus Names

H1N-What? Wading Through the Alphabet Soup of Flu Virus Names | Virology and Bioinformatics from Virology.ca | Scoop.it
Muddled about all the new flu viruses?

It’s hard to keep up with the changing names in the news. H1Nwhat? Bird flu. Pig flu. MERS. SARS. Here ...

Via Ed Rybicki
Chris Upton + helpers's insight:

Bloody bats just would have to be different!!!

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Ed Rybicki's curator insight, February 4, 7:22 AM

Great post on flu.

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Assessment of influenza virus hemagglutinin stalk-based immunity in ferrets

Therapeutic monoclonal antibodies that target the conserved stalk domain of the influenza virus hemagglutinin as well as stalk-based universal influenza virus vaccine strategies are being developed as promising countermeasures for influenza virus infections. The pan-H1 reactive monoclonal antibody 6F12 has been extensively characterized and shows broad efficacy against divergent H1N1 strains in the mouse model. Here we demonstrate its efficacy against a pandemic H1N1 challenge virus in the ferret model of influenza disease. Furthermore, we recently developed a universal influenza virus vaccine strategy based on chimeric hemagglutinin constructs that focuses the immune response towards the conserved stalk domain of the hemagglutinin. Here we set out to test this vaccination strategy in the ferret model. Both strategies, pre-treatment of animals with stalk-reactive monoclonal antibody as well as vaccination with chimeric hemagglutinin based constructs were able to significantly reduce viral titers in nasal turbinates, lungs and olfactory bulbs. In addition, vaccinated animals also showed reduced nasal wash viral titers. In summary both strategies showed efficacy in reducing viral loads after influenza virus challenge in the ferret model.

 
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A ‘Kill Switch’ For H7N9 and H5N1 ‘Gain-Of Function’ Influenza Viruses › That's Basic Science

A ‘Kill Switch’ For H7N9 and H5N1 ‘Gain-Of Function’ Influenza Viruses › That's Basic Science | Virology and Bioinformatics from Virology.ca | Scoop.it
 A report in Nature Biotechnology highlights a simple way to control gain-of-function flu viruses. Influenza A (H7N9) as viewed through an ...
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Cross-reactive human B cell and T cell epitopes between influenza A and B viruses

Influenza A and B viruses form different genera, which were originally distinguished by antigenic differences in their nucleoproteins and matrix 1 proteins.
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Inferring the causes of the three waves of the 1918 influenza pandemic in England and Wales

Past influenza pandemics appear to be characterized by multiple waves of incidence, but the mechanisms that account for this phenomenon remain unclear. We propose a simple epidemic model, which incorporates three factors that might contribute to the generation of multiple waves: (i) schools opening and closing, (ii) temperature changes during the outbreak, and (iii) changes in human behaviour in response to the outbreak. We fit this model to the reported influenza mortality during the 1918 pandemic in 334 UK administrative units and estimate the epidemiological parameters. We then use information criteria to evaluate how well these three factors explain the observed patterns of mortality. Our results indicate that all three factors are important but that behavioural responses had the largest effect. The parameter values that produce the best fit are biologically reasonable and yield epidemiological dynamics that match the observed data well.

 
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Sequence Analysis of In Vivo Defective Interfering-Like RNA of Influenza A H1N1 Pandemic Virus

Influenza virus defective interfering (DI) particles are naturally occurring noninfectious virions typically generated during in vitro serial passages in cell culture of the virus at a high multiplicity of infection. DI particles are recognized for the role they play in inhibiting viral replication and for the impact they have on the production of infectious virions. To date, influenza virus DI particles have been reported primarily as a phenomenon of cell culture and in experimentally infected embryonated chicken eggs. They have also been isolated from a respiratory infection of chickens. Using a sequencing approach, we characterize several subgenomic viral RNAs from human nasopharyngeal specimens infected with the influenza A(H1N1)pdm09 virus. The distribution of these in vivo-derived DI-like RNAs was similar to that of in vitro DIs, with the majority of the defective RNAs generated from the PB2 (segment 1) of the polymerase complex, followed by PB1 and PA. The lengths of the in vivo-derived DI-like segments also are similar to those of known in vitro DIs, and the in vivo-derived DI-like segments share internal deletions of the same segments. The presence of identical DI-like RNAs in patients linked by direct contact is compatible with transmission between them. The functional role of DI-like RNAs in natural infections remains to be established.

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Researchers strike gold with nanotech vaccine

Researchers strike gold with nanotech vaccine | Virology and Bioinformatics from Virology.ca | Scoop.it
Scientists in the US have developed a novel vaccination method that uses tiny gold particles to mimic a virus and carry specific proteins to the body’s specialist immune cells.
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Live attenuated influenza vaccine strains elicit a greater innate immune response than antigenically-matched seasonal influenza viruses

Live attenuated influenza vaccine strains elicit a greater innate immune response than antigenically-matched seasonal influenza viruses | Virology and Bioinformatics from Virology.ca | Scoop.it

Influenza viruses are global pathogens that infect approximately 10-20% of the world's population each year. Vaccines, including the live attenuated influenza vaccine (LAIV), are the best defense against influenza infections. The LAIV is a novel vaccine that actively replicates in the human nasal epithelium and elicits both mucosal and systemic protective immune responses. The differences in replication and innate immune responses following infection of human nasal epithelium with influenza seasonal wild type (WT) and LAIV viruses remain unknown. Using a model of primary differentiated human nasal epithelial cell (hNECs) cultures, we compared influenza WT and antigenically-matched cold adapted (CA) LAIV virus replication and the subsequent innate immune response including host cellular pattern recognition protein expression, host innate immune gene expression, secreted pro-inflammatory cytokine production, and intracellular viral RNA levels. Growth curves comparing virus replication between WT and LAIV strains revealed significantly less infectious virus production during LAIV compared with WT infection. Despite this disparity in infectious virus production the LAIV strains elicited a more robust innate immune response with increased expression of RIG-I, TLR-3, IFNβ, STAT-1, IRF-7, MxA, and IP-10. There were no differences in cytotoxicity between hNEC cultures infected with WT and LAIV strains as measured by basolateral levels of LDH. Elevated levels of intracellular viral RNA during LAIV as compared with WT virus infection of hNEC cultures at 33°C may explain the augmented innate immune response via the up-regulation of pattern recognition receptors and down-stream type I IFN expression. Taken together our results suggest that the decreased replication of LAIV strains in human nasal epithelial cells is associated with a robust innate immune response that differs from infection with seasonal influenza viruses, limits LAIV shedding and plays a role in the silent clinical phenotype seen in human LAIV inoculation.

 

Ed Rybicki's insight:

Well, of course they do: they engage ALL the levers making the immune system work!

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Structural Differences between the Avian and Human H7N9 Hemagglutinin Proteins Are Attributable to Modifications in Salt Bridge Formation: A Computational Study with Implications in Viral Evolution

Structural Differences between the Avian and Human H7N9 Hemagglutinin Proteins Are Attributable to Modifications in Salt Bridge Formation: A Computational Study with Implications in Viral Evolution | Virology and Bioinformatics from Virology.ca | Scoop.it
PLOS ONE: an inclusive, peer-reviewed, open-access resource from the PUBLIC LIBRARY OF SCIENCE. Reports of well-performed scientific studies from all disciplines freely available to the whole world.
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Evolution and Ecology of Influenza A Viruses.

Wild aquatic bird populations have long been considered the natural reservoir for influenza A viruses with virus transmission from these birds seeding other avian and mammalian hosts. While most evidence still supports this dogma, recent studies in bats have suggested other reservoir species may also exist. Extensive surveillance studies coupled with an enhanced awareness in response to H5N1 and pandemic 2009 H1N1 outbreaks is also revealing a growing list of animals susceptible to infection with influenza A viruses. Although in a relatively stable host-pathogen interaction in aquatic birds, antigenic, and genetic evolution of influenza A viruses often accompanies interspecies transmission as the virus adapts to a new host. The evolutionary changes in the new hosts result from a number of processes including mutation, reassortment, and recombination. Depending on host and virus these changes can be accompanied by disease outbreaks impacting wildlife, veterinary, and public health.

 

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Reconstruction of 1918-like avian influenza virus stirs concern over gain of function experiments

Reconstruction of 1918-like avian influenza virus stirs concern over gain of function experiments | Virology and Bioinformatics from Virology.ca | Scoop.it
The recent publication of new influenza virus gain of function studies from the laboratories of Kawaoka and Perez have unleashed another barrage of criticism.
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Identification, Characterization, and Natural Selection of Mutations Driving Airborne Transmission of A/H5N1 Virus: Cell

Identification, Characterization, and Natural Selection of Mutations Driving Airborne Transmission of A/H5N1 Virus: Cell | Virology and Bioinformatics from Virology.ca | Scoop.it

Recently, A/H5N1 influenza viruses were shown to acquire airborne transmissibility between ferrets upon targeted mutagenesis and virus passage. The critical genetic changes in airborne A/Indonesia/5/05 were not yet identified. Here, five substitutions proved to be sufficient to determine this airborne transmission phenotype. Substitutions in PB1 and PB2 collectively caused enhanced transcription and virus replication. One substitution increased HA thermostability and lowered the pH of membrane fusion. Two substitutions independently changed HA binding preference from α2,3-linked to α2,6-linked sialic acid receptors. The loss of a glycosylation site in HA enhanced overall binding to receptors. The acquired substitutions emerged early during ferret passage as minor variants and became dominant rapidly. Identification of substitutions that are essential for airborne transmission of avian influenza viruses between ferrets and their associated phenotypes advances our fundamental understanding of virus transmission and will increase the value of future surveillance programs and public health risk assessments.

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Threatwatch: Mother virus of China's deadly bird flu - health - 31 January 2014 - New Scientist

Threatwatch: Mother virus of China's deadly bird flu - health - 31 January 2014 - New Scientist | Virology and Bioinformatics from Virology.ca | Scoop.it
Ten years after H5N1, more deadly bird flu has emerged from China, most recently a strain called H10N8. Is it time to target the virus spawning them all?
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4th H7N9 avian influenza case confirmed in Hong Kong

4th H7N9 avian influenza case confirmed in Hong Kong | Virology and Bioinformatics from Virology.ca | Scoop.it
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Amino-acid substitutions in polymerase basic protein 2 gene contributes to the pathogenicity of the novel A/H7N9 influenza virus in mammalian hosts.

A novel avian-origin influenza A/H7N9 virus emerged in 2013 to cause more than 130 cases of zoonotic human disease with an overall case fatality of around 30% in cases detected. It has been shown that an amino acid change at the residue E627K of polymerase basic protein 2 (PB2) occurred frequently in the H7N9 isolates obtained from humans but not in viruses isolated from poultry. Although this mutation has been reported to confer increased mammalian pathogenicity in other avian influenza subtypes, it has not been experimentally investigated in the H7N9 virus. In this study, we determined the contribution of the PB2-E627K in H7N9 virus to the pathogenicity in mammalian hosts. In addition, the compensatory role of the other PB2 mutations at positions T271A, Q591K and D701N in H7N9 virus was investigated. We characterized the activity of polymerase complexes with these PB2 mutations and found that they enhance the polymerase activity in human 293T cells. The rescued mutants enhanced growth in mammalian cells in vitro. Mice infected with the H7N9 mutant containing avian signature PB2-627E showed marked decrease of disease severity (weight loss) and pathology compared to mice infected with the wild type strain (PB2-627K) or other PB2 mutants. Also, mutant with the PB2-627E showed lower virus replication and pro-inflammatory cytokine responses in the lungs of the virus-infected mice which may contribute to pathogenicity. Our results suggest that these amino acid substitutions contributes to mouse pathogenicity and mammalian adaptation.

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Real-time characterization of the molecular epidemiology of an influenza pandemic

Early characterization of the epidemiology and evolution of a pandemic is essential for determining the most appropriate interventions. During the 2009 H1N1 influenza A pandemic, public databases facilitated widespread sharing of genetic sequence data from the outset. We use Bayesian phylogenetics to simulate real-time estimates of the evolutionary rate, date of emergence and intrinsic growth rate (r0) of the pandemic from whole-genome sequences. We investigate the effects of temporal range of sampling and dataset size on the precision and accuracy of parameter estimation. Parameters can be accurately estimated as early as two months after the first reported case, from 100 genomes and the choice of growth model is important for accurate estimation ofr0. This demonstrates the utility of simple coalescent models to rapidly inform intervention strategies during a pandemic.

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Towards multiscale modeling of influenza infection

Aided by recent advances in computational power, algorithms, and higher fidelity data, increasingly detailed theoretical models of infection with influenza A virus are being developed. We review single scale models as they describe influenza infection from intracellular to global scales, and, in particular, we consider those models that capture details specific to influenza and can be used to link different scales. We discuss the few multiscale models of influenza infection that have been developed in this emerging field. In addition to discussing modeling approaches, we also survey biological data on influenza infection and transmission that is relevant for constructing influenza infection models. We envision that, in the future, multiscale models that capitalize on technical advances in experimental biology and high performance computing could be used to describe the large spatial scale epidemiology of influenza infection, evolution of the virus, and transmission between hosts more accurately.

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Pathogenesis and transmission of avian influenza A (H7N9) virus in ferrets and mice

On 29 March 2013, the Chinese Center for Disease Control and Prevention confirmed the first reported case of human infection with an avian influenza A(H7N9) virus1. The recent human infections with H7N9 virus, totalling over 130 cases with 39 fatalities to date, have been characterized by severe pulmonary disease and acute respiratory distress syndrome (ARDS)2. This is concerning because H7 viruses have typically been associated with ocular disease in humans, rather than severe respiratory disease3. This recent outbreak underscores the need to better understand the pathogenesis and transmission of these viruses in mammals. Here we assess the ability of A/Anhui/1/2013 and A/Shanghai/1/2013 (H7N9) viruses, isolated from fatal human cases, to cause disease in mice and ferrets and to transmit to naive animals. Both H7N9 viruses replicated to higher titre in human airway epithelial cells and in the respiratory tract of ferrets compared to a seasonal H3N2 virus. Moreover, the H7N9 viruses showed greater infectivity and lethality in mice compared to genetically related H7N9 and H9N2 viruses. The H7N9 viruses were readily transmitted to naive ferrets through direct contact but, unlike the seasonal H3N2 virus, did not transmit readily by respiratory droplets. The lack of efficient respiratory droplet transmission was corroborated by low receptor-binding specificity for human-like α2,6-linked sialosides. Our results indicate that H7N9 viruses have the capacity for efficient replication in mammals and human airway cells and highlight the need for continued public health surveillance of this emerging virus.

  
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BMC Medicine | Abstract | Comparing influenza vaccine efficacy against mismatched and matched strains: a systematic review and meta-analysis

Influenza vaccines are most effective when the antigens in the vaccine match those of circulating strains. However, antigens contained in the vaccines do not always match circulating strains.
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Mel Melendrez-Vallard's curator insight, June 27, 2013 4:21 PM

a good way to 'catch up'