Giuseppe
Emeritus
[In this post: (1) Research Articles Abstracts.
Contents:
(1.1) Estimation of the basic reproductive number ( R0) for epidemic, highly pathogenic avian influenza subtype H5N1 spread.
(1.2) Universal primer set for amplification and sequencing of HA0 cleavage sites of all influenza A viruses.
(1.3) Identification of two distinct bovine parainfluenza virus type 3 genotypes.
(1.4) Dual role of NOX2 in respiratory syncytial virus- and sendai virus-induced activation of NF-kappaB in airway epithelial cells.
(1.5) Prioritization of Influenza Pandemic Vaccination to Minimize Years of Life Lost.
(1.6) Effects of hemagglutinin-neuraminidase protein mutations on cell-cell fusion mediated by human parainfluenza type 2 virus.
(1.7) Amino Acid 226 in the Hemagglutinin of H4N6 Influenza Virus Determines Binding Affinity for {alpha}2,6-linked Sialic Acid and Infectivity Levels in Primary Swine and Human Respiratory Epithelial Cells.
(1.8) A simple mathematical model helps explain immunodominance of CD8 T-cells in influenza A infections.
(1.9) Vaccine preparedness--are we ready for the next influenza pandemic?
(1.10) Structure of coronavirus hemagglutinin-esterase offers insight into corona and influenza virus evolution.
(1.11) Maturation efficiency of viral glycoproteins in the ER impacts the production of influenza A virus.
See original abstracts at the source sites. EDITED.]
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(1.1): Epidemiol Infect. 2008 Jun 18:1-8. [Epub ahead of print]
Estimation of the basic reproductive number ( R0) for epidemic, highly pathogenic avian influenza subtype H5N1 spread.
Ward MP, Maftei D, Apostu C, Suru A. - College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, USA.
SUMMARY
Three different methods were used for estimating the basic reproductive number (R0) from data on 110 outbreaks of highly pathogenic avian influenza (HPAI) subtype H5N1 that occurred in village poultry in Romania, 12 May to 6 June 2006.
We assumed a village-level infectious period of 7 days.
The methods applied were GIS-based identification of nearest infectious neighbour (based on either Euclidean or road distance), the method of epidemic doubling time, and a susceptible-infectious (SI) modelling approach.
In general, the estimated basic reproductive numbers were consistent: 2.14, 1.95, 2.68 and 2.21, respectively.
Although the true basic reproductive number in this epidemic is unknown, results suggest that the use of a range of methods might be useful for characterizing epidemics of infectious diseases.
Once the basic reproductive number has been estimated, better control strategies and targeted surveillance programmes can be designed.
PMID: 18559127 [PubMed - as supplied by publisher]
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(1.2): J Clin Microbiol. 2008 Jun 18. [Epub ahead of print]
Universal primer set for amplification and sequencing of HA0 cleavage sites of all influenza A viruses.
Gall A, Hoffmann B, Harder T, Grund C, Beer M.- Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Suedufer 10, 17493 Greifswald - Insel Riems, Germany.
Sequence analysis of the endoproteolytic cleavage site within the haemagglutinin precursor protein HA0 is fundamental for studies on the molecular biology of influenza A viruses, in particular molecular pathotyping of subtype H5 and H7 isolates.
A current problem for routine diagnostics is the emergence of new strains of the H5, H7 or even other subtypes which escape detection by commonly used RT-PCR protocols.
Here, the first pan haemagglutinin reverse transcription polymerase chain reaction (PanHA RT-PCR) targeting the HA0 cleavage site of influenza A viruses of all 16 HA subtypes is reported.
The assay was assessed in comparison to H5 and H7 subtype-specific RT-PCRs for the HA0 cleavage site and a real-time RT-PCR detecting the M gene.
A panel of 92 influenza A viruses was used for validation.
Sequence data for influenza A viruses from 32 allantoic fluids and 11 swab diagnostic samples of all 16 HA subtypes were generated by direct sequencing of the PanHA RT-PCR products.
The results demonstrate that the new PanHA RT-PCR - followed by cycle sequencing - can complement existing methods and strengthen the reliability of influenza A virus diagnostics allowing both molecular pathotyping (H5, H7) and subtyping (non H5/H7) within a single approach.
PMID: 18562585 [PubMed - as supplied by publisher]
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(1.3): J Gen Virol. 2008 Jul;89(Pt 7):1643-8.
Identification of two distinct bovine parainfluenza virus type 3 genotypes.
Horwood PF, Gravel JL, Mahony TJ. - Department of Primary Industries and Fisheries, Ritchie Building 64A, Level 3, C Wing, Research Road, St Lucia, QLD 4072, Australia.
The partial gene sequencing of the matrix (M) protein from seven clinical isolates of bovine parainfluenza virus type 3 (BPIV-3), and the complete sequencing of a representative isolate (Q5592) was completed in this study.
Nucleotide sequence analysis was initiated because of the failure of in-house BPIV-3 RT-PCR methods to yield expected products for four of the isolates.
Phylogenetic reconstructions based on the nucleotide sequences for the M-protein and the entire genome, using all of the available BPIV-3 nucleotide sequences, demonstrated that there were two distinct BPIV-3 genotypes (BPIV-3a and BPIV-3b).
These newly identified genotypes have implications for the development of BPIV-3 molecular detection methods and may also impact on BPIV-3 vaccine formulations.
PMID: 18559934 [PubMed - in process]
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(1.4): J Immunol. 2008 May 15;180(10):6911-22.
Dual role of NOX2 in respiratory syncytial virus- and sendai virus-induced activation of NF-kappaB in airway epithelial cells.
Fink K, Duval A, Martel A, Soucy-Faulkner A, Grandvaux N. - Centre Hospitalier de l'Universit? de Montr?al Research Center- St-Luc Hospital and Institut National de la Sant? et de la Recherche M?dicale Unit? 743, Montreal, Quebec, Canada.
Human respiratory syncytial virus (RSV), a member of the Paramyxoviridae family, is the most important viral agent of pediatric respiratory tract disease worldwide.
Human airway epithelial cells (AEC) are the primary targets of RSV.
AEC are responsible for the secretion of a wide spectrum of cytokines and chemokines that are important mediators of the exacerbated airway inflammation triggered by the host in response to RSV infection.
NF-kappaB is a key transcription factor responsible for the regulation of cytokine and chemokine gene expression and thus represents a potential therapeutic target.
In the present study, we sought to delineate the role of RSV-induced reactive oxygen species in the regulation of the signaling pathways leading to NF-kappaB activation.
First, we demonstrate that besides the well-characterized IkappaBalpha-dependent pathway, phosphorylation of p65 at Ser(536) is an essential event regulating NF-kappaB activation in response to RSV in A549.
Using antioxidant and RNA-interference strategies, we show that a NADPH oxidase 2 (NOX2)-containing NADPH oxidase is an essential regulator of RSV-induced NF-kappaB activation.
Molecular analyses revealed that NOX2 acts upstream of both the phosphorylation of IkappaBalpha at Ser(32) and of p65 at Ser(536) in A549 and normal human bronchial epithelial cells.
Similar results were obtained in the context of infection by Sendai virus, thus demonstrating that the newly identified NOX2-dependent NF-kappaB activation pathway is not restricted to RSV among the Paramyxoviridae.
These results illustrate a previously unrecognized dual role of NOX2 in the regulation of NF-kappaB in response to RSV and Sendai virus in human AEC.
PMID: 18453612 [PubMed - indexed for MEDLINE]
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(1.5): J Infect Dis. 2008 Jun 17. [Epub ahead of print]
Prioritization of Influenza Pandemic Vaccination to Minimize Years of Life Lost.
Miller MA, Viboud C, Olson DR, Grais RF, Rabaa MA, Simonsen L. - 1Fogarty International Center, National Institutes of Health, Bethesda, Maryland; 2New York City Department of Health and Mental Hygiene, New York, New York; 3Department of Global Health, School of Public Health and Health Services, George Washington University, Washington, DC.
Background.
How to allocate limited vaccine supplies in the event of an influenza pandemic is currently under debate. Conventional vaccination strategies focus on those at highest risk for severe outcomes, including seniors, but do not consider
(1) the signature pandemic pattern in which mortality risk is shifted to younger ages,
(2) likely reduced vaccine response in seniors, and
(3) differences in remaining years of life with age.
Methods.
We integrated these factors to project the age-specific years of life lost (YLL) and saved in a future pandemic, on the basis of mortality patterns from 3 historical pandemics, age-specific vaccine efficacy, and the 2000 US population structure.
Results.
For a 1918-like scenario, the absolute mortality risk is highest in people <45 years old; in contrast, seniors (those >/=65 years old) have the highest mortality risk in the 1957 and 1968 scenarios. The greatest YLL savings would be achieved by targeting different age groups in each scenario; people <45 years old in the 1918 scenario, people 45-64 years old in the 1968 scenario, and people >45 years old in the 1957 scenario.
Conclusions.
Our findings shift the focus of pandemic vaccination strategies onto younger populations and illustrate the need for real-time surveillance of mortality patterns in a future pandemic. Flexible setting of vaccination priority is essential to minimize mortality.
PMID: 18558871 [PubMed - as supplied by publisher]
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(1.6): J Virol. 2008 Jun 18. [Epub ahead of print]
Effects of hemagglutinin-neuraminidase protein mutations on cell-cell fusion mediated by human parainfluenza type 2 virus.
Tsurudome M, Nishio M, Ito M, Tanahashi S, Kawano M, Komada H, Ito Y. - Department of Microbiology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, 1200 Matsumoto-Cho, Kasugai, Aichi 487-8501, Japan; Department of Microbiology, Suzuka University of Medical Science and Technology, 1001-1 Kishioka-Cho, Suzuka, Mie 510-0226, Japan.
The monoclonal antibody M1-1A, specific for the hemagglutinin-neuraminidase (HN) protein of human parainfluenza type 2 virus (HPIV2), blocks virus-induced cell-cell fusion without affecting the hemagglutinating and neuraminidase activities.
F13 is a neutralization escape variant selected with M1-1A and contains amino acid mutations N83Y and M186I in the HN protein, with no mutation in the fusion protein.
Intriguingly, F13 exhibits reduced ability to induce cell-cell fusion despite its multiple-step replication.
To investigate the potential role of HPIV2 HN protein in the regulation of cell-cell fusion, we introduced these mutations individually or in combination to the HN protein in the context of recombinant HPIV2.
Following infection at a low multiplicity, Vero cells infected with the mutant virus H-83/186, which carried both the N83Y and M186I mutations, remained as nonfused single cells at least for 24 h, whereas most of the cells infected with wild-type virus mediated prominent cell-cell fusion within 24 h.
On the other hand, the cells infected with the mutant virus, carrying either the H-83 or H-186 mutation, mediated cell-cell fusion yet less efficiently as compared to those infected with wild-type virus.
Irrespective of the ability to cause cell-cell fusion, however, every virus could infect all the cells in the culture within 48 h postinfection.
These results indicated that both the N83Y and M186I mutations in the HN protein are involved in the regulation of cell-cell fusion.
Notably, the limited cell-cell fusion by H-83/186 virus was greatly promoted by lysophosphatidic acid, a stimulator of Ras and Rho family GTPases.
PMID: 18562539 [PubMed - as supplied by publisher]
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(1.7): J Virol. 2008 Jun 11. [Epub ahead of print]
Amino Acid 226 in the Hemagglutinin of H4N6 Influenza Virus Determines Binding Affinity for {alpha}2,6-linked Sialic Acid and Infectivity Levels in Primary Swine and Human Respiratory Epithelial Cells.
Bateman AC, Busch MG, Karasin AI, Bovin N, Olsen CW. - Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA; Russian Academy of Sciences, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
Compared to avian-origin H4 subtype influenza viruses, avian-lineage H4N6 influenza viruses previously isolated from pigs differ at hemagglutinin amino acids 226 and 228.
Using a parental H4N6 swine isolate and hemagglutinin mutants (at residues 226 and/or 228), we determined that viruses with L226 had higher affinity for sialic acid (SA)-alpha2,6-galactose(Gal) and higher infectivity in primary swine and human respiratory epithelial cells, whereas viruses with Q226 had lower SAalpha2,6Gal affinity and lower infectivity in both cells.
Using specific neuraminidases, we found that irrespective of relative binding preferences, all of the influenza viruses examined utilize SAalpha2,6Gal to infect swine and human cells.
PMID: 18550676 [PubMed - as supplied by publisher]
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(1.8): J Virol. 2008 Jun 11. [Epub ahead of print]
A simple mathematical model helps explain immunodominance of CD8 T-cells in influenza A infections.
Handel A, Antia R. - Department of Biology, Emory University, Atlanta, GA 30322; Department of Biology, Emory University, Atlanta, GA 30322, USA.
Understanding immunodominance, the phenomenon that epitope-specific T-cells expand in an often distinct hierarchical fashion, is important for the design of T-cell based intervention strategies.
Several recent studies have investigated immunodominance of H2D(b) restricted CD8(+) T-cells specific for the nucleoprotein NP366 and acid polymerase PA224 epitopes during influenza A infection of C57BL/6 mice.
CD8(+) T-cells specific for these two epitopes are co-dominant during primary infection, NP366 dominates during secondary infection.
While a number of explanations for this observation have been proposed, none of them can fully account for all the observed data.
In this paper, we use a simple mathematical model to explain the seemingly inconsistent data.
We show that the dynamical interactions between CD8(+) T-cells and antigen presentation lead to a situation where CD8(+) T-cells are limiting during the initial response, whereas antigen is limiting in the secondary response.
This "numbers game" between antigen and CD8(+) T-cells can reproduce the observed immunodominance of the NP336 and PA224 specific CD8(+) T-cells, thereby explaining the reported experimental data.
PMID: 18550672 [PubMed - as supplied by publisher]
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(1.9): N Engl J Med. 2008 Jun 12;358(24):2540-3.
Vaccine preparedness--are we ready for the next influenza pandemic?
Wright PF. - Dartmouth Medical School, Hanover, NH, USA.
PMID: 18550873 [PubMed - in process]
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(1.10): Proc Natl Acad Sci U S A. 2008 Jun 11. [Epub ahead of print]
Structure of coronavirus hemagglutinin-esterase offers insight into corona and influenza virus evolution.
Zeng Q, Langereis MA, van Vliet AL, Huizinga EG, de Groot RJ. - Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Sciences, and.
The hemagglutinin-esterases (HEs) are a family of viral envelope glycoproteins that mediate reversible attachment to O-acetylated sialic acids by acting both as lectins and as receptor-destroying enzymes (RDEs).
Related HEs occur in influenza C, toro-, and coronaviruses, apparently as a result of relatively recent lateral gene transfer events.
Here, we report the crystal structure of a coronavirus (CoV) HE in complex with its receptor.
We show that CoV HE arose from an influenza C-like HE fusion protein (HEF). In the process, HE was transformed from a trimer into a dimer, whereas remnants of the fusion domain were adapted to establish novel monomer-monomer contacts.
Whereas the structural design of the RDE-acetylesterase domain remained unaltered, the HE receptor-binding domain underwent remodeling to such extent that the ligand is now bound in opposite orientation.
This is surprising, because the architecture of the HEF site was preserved in influenza A HA over a much larger evolutionary distance, a switch in receptor specificity and extensive antigenic variation notwithstanding.
Apparently, HA and HEF are under more stringent selective constraints than HE, limiting their exploration of alternative binding-site topologies.
We attribute the plasticity of the CoV HE receptor-binding site to evolutionary flexibility conferred by functional redundancy between HE and its companion spike protein S.
Our findings offer unique insights into the structural and functional consequences of independent protein evolution after interviral gene exchange and open potential avenues to broad-spectrum antiviral drug design.
PMID: 18550812 [PubMed - as supplied by publisher]
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(1.11): Virus Res. 2008 Jun 10. [Epub ahead of print]
Maturation efficiency of viral glycoproteins in the ER impacts the production of influenza A virus.
Ueda M, Yamate M, Du A, Daidoji T, Okuno Y, Ikuta K, Nakaya T. - Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
We have studied which steps are enhanced in the infectious cycle of influenza A virus in Madin-Darby canine kidney (MDCK) cells, a cell line investigated for use in the production of an influenza vaccine because of its ability to yield high levels of virus.
We have confirmed that MDCK had the highest production levels of virions among several cell lines early in the infection.
Influenza A virus showed similar levels of viral genomic RNA replication, mRNA transcription, and protein expression in A549 as in MDCK.
Thus, we focused on the post-translational transport of viral glycoproteins from the endoplasmic reticulum (ER) to the plasma membrane.
Comparative characterization revealed more efficient processing in the folding and maturation of hemagglutinin and neuraminidase in the ER in MDCK than in A549.
Also, the subsequent transport of these glycoproteins to the plasma membrane occurred much earlier in MDCK.
These results indicate that the folding and maturation efficiencies of viral glycoproteins in the ER impact the efficiency with which influenza A viral particles are produced.
PMID: 18550190 [PubMed - as supplied by publisher]
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Contents:
(1.1) Estimation of the basic reproductive number ( R0) for epidemic, highly pathogenic avian influenza subtype H5N1 spread.
(1.2) Universal primer set for amplification and sequencing of HA0 cleavage sites of all influenza A viruses.
(1.3) Identification of two distinct bovine parainfluenza virus type 3 genotypes.
(1.4) Dual role of NOX2 in respiratory syncytial virus- and sendai virus-induced activation of NF-kappaB in airway epithelial cells.
(1.5) Prioritization of Influenza Pandemic Vaccination to Minimize Years of Life Lost.
(1.6) Effects of hemagglutinin-neuraminidase protein mutations on cell-cell fusion mediated by human parainfluenza type 2 virus.
(1.7) Amino Acid 226 in the Hemagglutinin of H4N6 Influenza Virus Determines Binding Affinity for {alpha}2,6-linked Sialic Acid and Infectivity Levels in Primary Swine and Human Respiratory Epithelial Cells.
(1.8) A simple mathematical model helps explain immunodominance of CD8 T-cells in influenza A infections.
(1.9) Vaccine preparedness--are we ready for the next influenza pandemic?
(1.10) Structure of coronavirus hemagglutinin-esterase offers insight into corona and influenza virus evolution.
(1.11) Maturation efficiency of viral glycoproteins in the ER impacts the production of influenza A virus.
See original abstracts at the source sites. EDITED.]
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(1.1): Epidemiol Infect. 2008 Jun 18:1-8. [Epub ahead of print]
Estimation of the basic reproductive number ( R0) for epidemic, highly pathogenic avian influenza subtype H5N1 spread.
Ward MP, Maftei D, Apostu C, Suru A. - College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, USA.
SUMMARY
Three different methods were used for estimating the basic reproductive number (R0) from data on 110 outbreaks of highly pathogenic avian influenza (HPAI) subtype H5N1 that occurred in village poultry in Romania, 12 May to 6 June 2006.
We assumed a village-level infectious period of 7 days.
The methods applied were GIS-based identification of nearest infectious neighbour (based on either Euclidean or road distance), the method of epidemic doubling time, and a susceptible-infectious (SI) modelling approach.
In general, the estimated basic reproductive numbers were consistent: 2.14, 1.95, 2.68 and 2.21, respectively.
Although the true basic reproductive number in this epidemic is unknown, results suggest that the use of a range of methods might be useful for characterizing epidemics of infectious diseases.
Once the basic reproductive number has been estimated, better control strategies and targeted surveillance programmes can be designed.
PMID: 18559127 [PubMed - as supplied by publisher]
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(1.2): J Clin Microbiol. 2008 Jun 18. [Epub ahead of print]
Universal primer set for amplification and sequencing of HA0 cleavage sites of all influenza A viruses.
Gall A, Hoffmann B, Harder T, Grund C, Beer M.- Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Suedufer 10, 17493 Greifswald - Insel Riems, Germany.
Sequence analysis of the endoproteolytic cleavage site within the haemagglutinin precursor protein HA0 is fundamental for studies on the molecular biology of influenza A viruses, in particular molecular pathotyping of subtype H5 and H7 isolates.
A current problem for routine diagnostics is the emergence of new strains of the H5, H7 or even other subtypes which escape detection by commonly used RT-PCR protocols.
Here, the first pan haemagglutinin reverse transcription polymerase chain reaction (PanHA RT-PCR) targeting the HA0 cleavage site of influenza A viruses of all 16 HA subtypes is reported.
The assay was assessed in comparison to H5 and H7 subtype-specific RT-PCRs for the HA0 cleavage site and a real-time RT-PCR detecting the M gene.
A panel of 92 influenza A viruses was used for validation.
Sequence data for influenza A viruses from 32 allantoic fluids and 11 swab diagnostic samples of all 16 HA subtypes were generated by direct sequencing of the PanHA RT-PCR products.
The results demonstrate that the new PanHA RT-PCR - followed by cycle sequencing - can complement existing methods and strengthen the reliability of influenza A virus diagnostics allowing both molecular pathotyping (H5, H7) and subtyping (non H5/H7) within a single approach.
PMID: 18562585 [PubMed - as supplied by publisher]
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(1.3): J Gen Virol. 2008 Jul;89(Pt 7):1643-8.
Identification of two distinct bovine parainfluenza virus type 3 genotypes.
Horwood PF, Gravel JL, Mahony TJ. - Department of Primary Industries and Fisheries, Ritchie Building 64A, Level 3, C Wing, Research Road, St Lucia, QLD 4072, Australia.
The partial gene sequencing of the matrix (M) protein from seven clinical isolates of bovine parainfluenza virus type 3 (BPIV-3), and the complete sequencing of a representative isolate (Q5592) was completed in this study.
Nucleotide sequence analysis was initiated because of the failure of in-house BPIV-3 RT-PCR methods to yield expected products for four of the isolates.
Phylogenetic reconstructions based on the nucleotide sequences for the M-protein and the entire genome, using all of the available BPIV-3 nucleotide sequences, demonstrated that there were two distinct BPIV-3 genotypes (BPIV-3a and BPIV-3b).
These newly identified genotypes have implications for the development of BPIV-3 molecular detection methods and may also impact on BPIV-3 vaccine formulations.
PMID: 18559934 [PubMed - in process]
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(1.4): J Immunol. 2008 May 15;180(10):6911-22.
Dual role of NOX2 in respiratory syncytial virus- and sendai virus-induced activation of NF-kappaB in airway epithelial cells.
Fink K, Duval A, Martel A, Soucy-Faulkner A, Grandvaux N. - Centre Hospitalier de l'Universit? de Montr?al Research Center- St-Luc Hospital and Institut National de la Sant? et de la Recherche M?dicale Unit? 743, Montreal, Quebec, Canada.
Human respiratory syncytial virus (RSV), a member of the Paramyxoviridae family, is the most important viral agent of pediatric respiratory tract disease worldwide.
Human airway epithelial cells (AEC) are the primary targets of RSV.
AEC are responsible for the secretion of a wide spectrum of cytokines and chemokines that are important mediators of the exacerbated airway inflammation triggered by the host in response to RSV infection.
NF-kappaB is a key transcription factor responsible for the regulation of cytokine and chemokine gene expression and thus represents a potential therapeutic target.
In the present study, we sought to delineate the role of RSV-induced reactive oxygen species in the regulation of the signaling pathways leading to NF-kappaB activation.
First, we demonstrate that besides the well-characterized IkappaBalpha-dependent pathway, phosphorylation of p65 at Ser(536) is an essential event regulating NF-kappaB activation in response to RSV in A549.
Using antioxidant and RNA-interference strategies, we show that a NADPH oxidase 2 (NOX2)-containing NADPH oxidase is an essential regulator of RSV-induced NF-kappaB activation.
Molecular analyses revealed that NOX2 acts upstream of both the phosphorylation of IkappaBalpha at Ser(32) and of p65 at Ser(536) in A549 and normal human bronchial epithelial cells.
Similar results were obtained in the context of infection by Sendai virus, thus demonstrating that the newly identified NOX2-dependent NF-kappaB activation pathway is not restricted to RSV among the Paramyxoviridae.
These results illustrate a previously unrecognized dual role of NOX2 in the regulation of NF-kappaB in response to RSV and Sendai virus in human AEC.
PMID: 18453612 [PubMed - indexed for MEDLINE]
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(1.5): J Infect Dis. 2008 Jun 17. [Epub ahead of print]
Prioritization of Influenza Pandemic Vaccination to Minimize Years of Life Lost.
Miller MA, Viboud C, Olson DR, Grais RF, Rabaa MA, Simonsen L. - 1Fogarty International Center, National Institutes of Health, Bethesda, Maryland; 2New York City Department of Health and Mental Hygiene, New York, New York; 3Department of Global Health, School of Public Health and Health Services, George Washington University, Washington, DC.
Background.
How to allocate limited vaccine supplies in the event of an influenza pandemic is currently under debate. Conventional vaccination strategies focus on those at highest risk for severe outcomes, including seniors, but do not consider
(1) the signature pandemic pattern in which mortality risk is shifted to younger ages,
(2) likely reduced vaccine response in seniors, and
(3) differences in remaining years of life with age.
Methods.
We integrated these factors to project the age-specific years of life lost (YLL) and saved in a future pandemic, on the basis of mortality patterns from 3 historical pandemics, age-specific vaccine efficacy, and the 2000 US population structure.
Results.
For a 1918-like scenario, the absolute mortality risk is highest in people <45 years old; in contrast, seniors (those >/=65 years old) have the highest mortality risk in the 1957 and 1968 scenarios. The greatest YLL savings would be achieved by targeting different age groups in each scenario; people <45 years old in the 1918 scenario, people 45-64 years old in the 1968 scenario, and people >45 years old in the 1957 scenario.
Conclusions.
Our findings shift the focus of pandemic vaccination strategies onto younger populations and illustrate the need for real-time surveillance of mortality patterns in a future pandemic. Flexible setting of vaccination priority is essential to minimize mortality.
PMID: 18558871 [PubMed - as supplied by publisher]
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(1.6): J Virol. 2008 Jun 18. [Epub ahead of print]
Effects of hemagglutinin-neuraminidase protein mutations on cell-cell fusion mediated by human parainfluenza type 2 virus.
Tsurudome M, Nishio M, Ito M, Tanahashi S, Kawano M, Komada H, Ito Y. - Department of Microbiology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, 1200 Matsumoto-Cho, Kasugai, Aichi 487-8501, Japan; Department of Microbiology, Suzuka University of Medical Science and Technology, 1001-1 Kishioka-Cho, Suzuka, Mie 510-0226, Japan.
The monoclonal antibody M1-1A, specific for the hemagglutinin-neuraminidase (HN) protein of human parainfluenza type 2 virus (HPIV2), blocks virus-induced cell-cell fusion without affecting the hemagglutinating and neuraminidase activities.
F13 is a neutralization escape variant selected with M1-1A and contains amino acid mutations N83Y and M186I in the HN protein, with no mutation in the fusion protein.
Intriguingly, F13 exhibits reduced ability to induce cell-cell fusion despite its multiple-step replication.
To investigate the potential role of HPIV2 HN protein in the regulation of cell-cell fusion, we introduced these mutations individually or in combination to the HN protein in the context of recombinant HPIV2.
Following infection at a low multiplicity, Vero cells infected with the mutant virus H-83/186, which carried both the N83Y and M186I mutations, remained as nonfused single cells at least for 24 h, whereas most of the cells infected with wild-type virus mediated prominent cell-cell fusion within 24 h.
On the other hand, the cells infected with the mutant virus, carrying either the H-83 or H-186 mutation, mediated cell-cell fusion yet less efficiently as compared to those infected with wild-type virus.
Irrespective of the ability to cause cell-cell fusion, however, every virus could infect all the cells in the culture within 48 h postinfection.
These results indicated that both the N83Y and M186I mutations in the HN protein are involved in the regulation of cell-cell fusion.
Notably, the limited cell-cell fusion by H-83/186 virus was greatly promoted by lysophosphatidic acid, a stimulator of Ras and Rho family GTPases.
PMID: 18562539 [PubMed - as supplied by publisher]
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(1.7): J Virol. 2008 Jun 11. [Epub ahead of print]
Amino Acid 226 in the Hemagglutinin of H4N6 Influenza Virus Determines Binding Affinity for {alpha}2,6-linked Sialic Acid and Infectivity Levels in Primary Swine and Human Respiratory Epithelial Cells.
Bateman AC, Busch MG, Karasin AI, Bovin N, Olsen CW. - Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA; Russian Academy of Sciences, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
Compared to avian-origin H4 subtype influenza viruses, avian-lineage H4N6 influenza viruses previously isolated from pigs differ at hemagglutinin amino acids 226 and 228.
Using a parental H4N6 swine isolate and hemagglutinin mutants (at residues 226 and/or 228), we determined that viruses with L226 had higher affinity for sialic acid (SA)-alpha2,6-galactose(Gal) and higher infectivity in primary swine and human respiratory epithelial cells, whereas viruses with Q226 had lower SAalpha2,6Gal affinity and lower infectivity in both cells.
Using specific neuraminidases, we found that irrespective of relative binding preferences, all of the influenza viruses examined utilize SAalpha2,6Gal to infect swine and human cells.
PMID: 18550676 [PubMed - as supplied by publisher]
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(1.8): J Virol. 2008 Jun 11. [Epub ahead of print]
A simple mathematical model helps explain immunodominance of CD8 T-cells in influenza A infections.
Handel A, Antia R. - Department of Biology, Emory University, Atlanta, GA 30322; Department of Biology, Emory University, Atlanta, GA 30322, USA.
Understanding immunodominance, the phenomenon that epitope-specific T-cells expand in an often distinct hierarchical fashion, is important for the design of T-cell based intervention strategies.
Several recent studies have investigated immunodominance of H2D(b) restricted CD8(+) T-cells specific for the nucleoprotein NP366 and acid polymerase PA224 epitopes during influenza A infection of C57BL/6 mice.
CD8(+) T-cells specific for these two epitopes are co-dominant during primary infection, NP366 dominates during secondary infection.
While a number of explanations for this observation have been proposed, none of them can fully account for all the observed data.
In this paper, we use a simple mathematical model to explain the seemingly inconsistent data.
We show that the dynamical interactions between CD8(+) T-cells and antigen presentation lead to a situation where CD8(+) T-cells are limiting during the initial response, whereas antigen is limiting in the secondary response.
This "numbers game" between antigen and CD8(+) T-cells can reproduce the observed immunodominance of the NP336 and PA224 specific CD8(+) T-cells, thereby explaining the reported experimental data.
PMID: 18550672 [PubMed - as supplied by publisher]
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(1.9): N Engl J Med. 2008 Jun 12;358(24):2540-3.
Vaccine preparedness--are we ready for the next influenza pandemic?
Wright PF. - Dartmouth Medical School, Hanover, NH, USA.
PMID: 18550873 [PubMed - in process]
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(1.10): Proc Natl Acad Sci U S A. 2008 Jun 11. [Epub ahead of print]
Structure of coronavirus hemagglutinin-esterase offers insight into corona and influenza virus evolution.
Zeng Q, Langereis MA, van Vliet AL, Huizinga EG, de Groot RJ. - Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Sciences, and.
The hemagglutinin-esterases (HEs) are a family of viral envelope glycoproteins that mediate reversible attachment to O-acetylated sialic acids by acting both as lectins and as receptor-destroying enzymes (RDEs).
Related HEs occur in influenza C, toro-, and coronaviruses, apparently as a result of relatively recent lateral gene transfer events.
Here, we report the crystal structure of a coronavirus (CoV) HE in complex with its receptor.
We show that CoV HE arose from an influenza C-like HE fusion protein (HEF). In the process, HE was transformed from a trimer into a dimer, whereas remnants of the fusion domain were adapted to establish novel monomer-monomer contacts.
Whereas the structural design of the RDE-acetylesterase domain remained unaltered, the HE receptor-binding domain underwent remodeling to such extent that the ligand is now bound in opposite orientation.
This is surprising, because the architecture of the HEF site was preserved in influenza A HA over a much larger evolutionary distance, a switch in receptor specificity and extensive antigenic variation notwithstanding.
Apparently, HA and HEF are under more stringent selective constraints than HE, limiting their exploration of alternative binding-site topologies.
We attribute the plasticity of the CoV HE receptor-binding site to evolutionary flexibility conferred by functional redundancy between HE and its companion spike protein S.
Our findings offer unique insights into the structural and functional consequences of independent protein evolution after interviral gene exchange and open potential avenues to broad-spectrum antiviral drug design.
PMID: 18550812 [PubMed - as supplied by publisher]
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(1.11): Virus Res. 2008 Jun 10. [Epub ahead of print]
Maturation efficiency of viral glycoproteins in the ER impacts the production of influenza A virus.
Ueda M, Yamate M, Du A, Daidoji T, Okuno Y, Ikuta K, Nakaya T. - Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
We have studied which steps are enhanced in the infectious cycle of influenza A virus in Madin-Darby canine kidney (MDCK) cells, a cell line investigated for use in the production of an influenza vaccine because of its ability to yield high levels of virus.
We have confirmed that MDCK had the highest production levels of virions among several cell lines early in the infection.
Influenza A virus showed similar levels of viral genomic RNA replication, mRNA transcription, and protein expression in A549 as in MDCK.
Thus, we focused on the post-translational transport of viral glycoproteins from the endoplasmic reticulum (ER) to the plasma membrane.
Comparative characterization revealed more efficient processing in the folding and maturation of hemagglutinin and neuraminidase in the ER in MDCK than in A549.
Also, the subsequent transport of these glycoproteins to the plasma membrane occurred much earlier in MDCK.
These results indicate that the folding and maturation efficiencies of viral glycoproteins in the ER impact the efficiency with which influenza A viral particles are produced.
PMID: 18550190 [PubMed - as supplied by publisher]
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