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Find video protocols related to scientific articles indexed in Pubmed.
Molecular determinants of pathogenicity in the polymerase complex.
Curr. Top. Microbiol. Immunol.
PUBLISHED: 07-19-2014
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Viral pathogenesis involves numerous interactions between viral and cellular factors. In recent years, the influenza virus polymerase complex has emerged as a major determinant of interspecies transmission and pathogenicity. The viral RNA-dependent RNA polymerase, in concert with the nucleoprotein, mediates transcription and replication of the viral RNA genome in the nucleus of the infected cell. The activity by which the viral polymerase complex performs these processes in mammalian cells is considered to be a major contributor to viral pathogenicity in mammals. In this chapter, we summarise our current understanding on the pathogenicity determinants in the viral polymerase complex and highlight some of its cellular interaction partners. We particularly discuss the role of importin-? isoforms in host adaptation and pathogenesis as well as the role of the viral polymerase in regulating cellular responses to viral infection.
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Sex, immunity and influenza.
J. Infect. Dis.
PUBLISHED: 06-27-2014
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Sex-specific endocrine and immune responses are widely recognized to account for differential disease outcomes between females and males. Surprisingly, sex-specific risk assessments for influenza, a viral pathogen that affects human populations worldwide through seasonal epidemics and irregular occurring pandemics, are sparse and-if available-ambiguous. To date, this precludes proposing an unequivocal sex-dependent susceptibility to influenza. However, one undisputable observation recurrently confirmed during influenza seasons of the last decades is the significantly increased risk for pregnant women. This increased risk is likely attributable to the contradictory demands for the maternal immune system to adapt to pregnancy and to simultaneously mount an immune response to clear the influenza virus infection. Here, we review published evidence on the potential association between sex on influenza risk and propose that future epidemiologic studies should carefully dissect surveillance data for sex-specific effects. Moreover, we propose potential mechanisms involved in enhanced risk for severe influenza during pregnancy that could be studied to identify causal pathways.
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Sumoylation of influenza A virus nucleoprotein is essential for intracellular trafficking and virus growth.
J. Virol.
PUBLISHED: 06-11-2014
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Viruses take advantage of host posttranslational modifications for their own benefit. It was recently reported that influenza A virus proteins interact extensively with the host sumoylation system. Thereby, several viral proteins, including NS1 and M1, are sumoylated to facilitate viral replication. However, to what extent sumoylation is exploited by influenza A virus is not fully understood. In this study, we found that influenza A virus nucleoprotein (NP) is a bona fide target of sumoylation in both NP-transfected cells and virus-infected cells. We further found that NP is sumoylated at the two most N-terminal residues, lysines 4 and 7, and that sumoylation at lysine 7 of NP is highly conserved across different influenza A virus subtypes and strains, including the recently emerged human H7N9 virus. While NP stability and polymerase activity are little affected by sumoylation, the NP sumoylation-defective WSN-NPK4,7R virus exhibited early cytoplasmic localization of NP. The growth of the WSN-NPK4,7R virus was highly attenuated compared to that of the wild-type WSN virus, and the lysine residue at position 7 is indispensable for the virus's survival, as illustrated by the rapid emergence of revertant viruses. Thus, sumoylation of influenza A virus NP is essential for intracellular trafficking of NP and for virus growth, illustrating sumoylation as a crucial strategy extensively exploited by influenza A virus for survival in its host.
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PB2 mutations D701N and S714R promote adaptation of an influenza H5N1 virus to a mammalian host.
J. Virol.
PUBLISHED: 06-04-2014
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Mutation D701N in the PB2 protein is known to play a prominent role in the adaptation of avian influenza A viruses to mammalian hosts. In contrast, little is known about the nearby mutations S714I and S714R, which have been observed in some avian influenza viruses highly pathogenic for mammals. We have generated recombinant H5N1 viruses with PB2 displaying the avian signature 701D or the mammalian signature 701N and serine, isoleucine, and arginine at position 714 and compared them for polymerase activity and virus growth in avian and mammalian cells, as well as for pathogenicity in mice. Mutation D701N led to an increase in polymerase activity and replication efficiency in mammalian cells and in mouse pathogenicity, and this increase was significantly enhanced when mutation D701N was combined with mutation S714R. Stimulation by mutation S714I was less distinct. These observations indicate that PB2 mutation S714R, in combination with the mammalian signature at position 701, has the potential to promote the adaptation of an H5N1 virus to a mammalian host.
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Importin-?7 is required for enhanced influenza A virus replication in the alveolar epithelium and severe lung damage in mice.
J. Virol.
PUBLISHED: 05-14-2014
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Influenza A viruses recruit components of the nuclear import pathway to enter the host cell nucleus and promote viral replication. Here, we analyzed the role of the nuclear import factor importin-?7 in H1N1 influenza virus pulmonary tropism by using various ex vivo imaging techniques (magnetic resonance imaging, confocal laser scanning microscopy, and correlative light-electron microscopy). We infected importin-?7 gene-deficient (?7(-/-)) mice with a recombinant H1N1 influenza virus and compared the in vivo viral kinetics with those in wild-type (WT) mice. In WT mice, influenza virus replication in the bronchial and alveolar epithelium already occurred a few days after infection. Accordingly, extensive mononuclear infiltration and alveolar destruction were present in the lungs of infected WT mice, followed by 100% lethality. Conversely, in ?7(-/-) mice, virus replication was restricted mostly to the bronchial epithelium with marginal alveolar infection, resulting in significantly reduced lung damage and enhanced animal survival. To investigate the host immune response during alveolar virus replication, we studied the role of primary macrophages in virus propagation and clearance. The ability of macrophages to support or clear the virus infection, as well as the host cellular immune responses, did not significantly differ between WT and ?7(-/-) mice. However, cytokine and chemokine responses were generally elevated in WT mice, likely reflective of increased viral replication in the lung. In summary, these data show that a cellular factor, importin-?7, is required for enhanced virus replication in the alveolar epithelium, resulting in elevated cytokine and chemokine levels, extensive mononuclear infiltration, and thus, severe pneumonia and enhanced virulence in mice. Importance: Influenza A viruses are respiratory pathogens that may cause pneumonia in humans. Viral infection and replication in the alveoli of the respiratory tract are believed to be crucial for the development of the acute respiratory distress syndrome associated with fatal outcomes in influenza virus-infected patients. Here, we report the requirement of a cellular factor, importin-?7, for efficient virus replication in the alveolar epithelium of mice. Using complementary ex vivo imaging approaches, we show that influenza virus replication is restricted to the bronchial epithelium, followed by enhanced survival in importin-?7-deficient mice. In contrast, the presence of this gene results in enhanced virus replication in the alveoli, elevated cytokine and chemokine responses, mononuclear infiltration, alveolar destruction, and 100% lethality in wild-type mice. Taken together, our results show that importin-?7 is particularly required for virus replication in the alveolar epithelium in association with severe pneumonia and death in mice.
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TMPRSS2 is a host factor that is essential for pneumotropism and pathogenicity of H7N9 influenza A virus in mice.
J. Virol.
PUBLISHED: 02-12-2014
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Cleavage of the hemagglutinin (HA) by host proteases is essential for the infectivity of influenza viruses. Here, we analyzed the role of the serine protease TMPRSS2, which activates HA in the human respiratory tract, in pathogenesis in a mouse model. Replication of the human H7N9 isolate A/Anhui/1/13 and of human H1N1 and H3N2 viruses was compared in TMPRSS2 knockout (TMPRSS2(-/-)) and wild-type (WT) mice. Knockout of TMPRSS2 expression inhibited H7N9 influenza virus replication in explants of murine tracheas, bronchi, and lungs. H1N1 virus replication was also strongly suppressed in airway explants of TMPRSS2(-/-) mice, while H3N2 virus replication was only marginally affected. H7N9 and H1N1 viruses were apathogenic in TMPRSS2(-/-) mice, whereas WT mice developed severe disease with mortality rates of 100% and 20%, respectively. In contrast, all H3N2 infected TMPRSS2(-/-) and WT mice succumbed to lethal infection. Cleavage analysis showed that H7 and H1 are efficiently activated by TMPRSS2, whereas H3 is less susceptible to the protease. Our data demonstrate that TMPRSS2 is a host factor that is essential for pneumotropism and pathogenicity of H7N9 and H1N1 influenza virus in mice. In contrast, replication of H3N2 virus appears to depend on another, not yet identified protease, supporting the concept that human influenza viruses differ in protease specificity.
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Novel avian-origin influenza A (H7N9) virus attachment to the respiratory tract of five animal models.
J. Virol.
PUBLISHED: 01-29-2014
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We determined the pattern of attachment of the avian-origin H7N9 influenza viruses A/Anhui/1/2013 and A/Shanghai/1/2013 to the respiratory tract in ferrets, macaques, mice, pigs, and guinea pigs and compared it to that in humans. The H7N9 attachment pattern in macaques, mice, and to a lesser extent pigs and guinea pigs resembled that in humans more closely than the attachment pattern in ferrets. This information contributes to our knowledge of the different animal models for influenza.
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Fragile X mental retardation protein stimulates ribonucleoprotein assembly of influenza A virus.
Nat Commun
PUBLISHED: 01-15-2014
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The ribonucleoprotein (RNP) of the influenza A virus is responsible for the transcription and replication of viral RNA in the nucleus. These processes require interplay between host factors and RNP components. Here, we report that the Fragile X mental retardation protein (FMRP) targets influenza virus RNA synthesis machinery and facilitates virus replication both in cell culture and in mice. We demonstrate that FMRP transiently associates with viral RNP and stimulates viral RNP assembly through RNA-mediated interaction with the nucleoprotein. Furthermore, the KH2 domain of FMRP mediates its association with the nucleoprotein. A point mutation (I304N) in the KH2 domain, identified from a Fragile X syndrome patient, disrupts the FMRP-nucleoprotein association and abolishes the ability of FMRP to participate in viral RNP assembly. We conclude that FMRP is a critical host factor used by influenza viruses to facilitate viral RNP assembly. Our observation reveals a mechanism of influenza virus RNA synthesis and provides insights into FMRP functions.
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A new class of synthetic anti-lipopolysaccharide peptides inhibits influenza A virus replication by blocking cellular attachment.
Antiviral Res.
PUBLISHED: 01-08-2014
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Influenza A viruses are a continuous threat to human health as illustrated by the 2009 H1N1 pandemic. Since circulating influenza virus strains become increasingly resistant against currently available drugs, the development of novel antivirals is urgently needed. Here, we have evaluated a recently described new class of broad-spectrum antiviral peptides (synthetic anti-lipopolysaccharide peptides; SALPs) for their potential to inhibit influenza virus replication in vitro and in vivo. We found that particularly SALP PEP 19-2.5 shows high binding affinities for the influenza virus receptor molecule, N-Acetylneuraminic acid, leading to impaired viral attachment and cellular entry. As a result, replication of several influenza virus subtypes (H7N7, H3N2 and 2009 pandemic H1N1) was strongly reduced. Furthermore, mice co-treated with PEP 19-2.5 were protected against an otherwise 100% lethal H7N7 influenza virus infection. These findings show that SALPs exhibit antiviral activity against influenza viruses by blocking virus attachment and entry into host cells. Thus, SALPs present a new class of broad-spectrum antiviral peptides for further development for influenza virus therapy.
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The nuclear import machinery is a determinant of influenza virus host adaptation.
Bioessays
PUBLISHED: 11-19-2013
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After viral entry into the cell, the nuclear envelope poses a major cellular barrier that needs to be overcome upon adaptation of highly pathogenic avian influenza viruses (HPAIV) to the new host. To ensure efficient viral transcription and replication in the nucleus of the host cell, the viral polymerase complex of avian influenza viruses needs to switch from recognition of avian to mammalian components of the nuclear import machinery. Recent evidence suggests that influenza viruses have evolved different mechanisms to utilize importin-? isoforms as components of this machinery, bridging pre- and post-nuclear import on both sides of the nuclear envelope.
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Mucosal Reactive Oxygen Species Are Required for Antiviral Response: Role of Duox in Influenza A Virus Infection.
Antioxid. Redox Signal.
PUBLISHED: 10-15-2013
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Abstract Aims: Influenza A virus (IAV), a major airborne pathogen, is closely associated with significant morbidity and mortality. The primary target for influenza virus replication is the respiratory epithelium, which reacts to infection by mounting a multifaceted antiviral response. A part of this mucosal host defense is the generation of reactive oxygen species (ROS) by NADPH oxidases. Duox1 and Duox2 are the main ROS-producing enzymes in the airway epithelium, but their contribution to mammalian host defense is still ill defined. Results: To gain a better understanding of Duox function in respiratory tract infections, human differentiated lung epithelial cells and an animal model were used to monitor the effect of epithelial ROS on IAV propagation. IAV infection led to coordinated up-regulation of Duox2 and Duox-mediated ROS generation. Interference with H2O2 production and ROS signaling by oxidase inhibition or H2O2 decomposition augmented IAV replication. A nuclear pool of Duox enzymes participated in the regulation of the spliceosome, which is critical for alternative splicing of viral transcripts and controls the assembly of viable virions. In vivo silencing of Duox increased the viral load on intranasal infection with 2009 pandemic H1N1 influenza virus. Innovation: This is the first study conclusively linking Duox NADPH oxidases with the antiviral mammalian immune response. Further, ROS generated by Duox enzymes localized adjacent to nuclear speckles altered the splicing of viral genes. Conclusion: Duox-derived ROS are host protective and essential for counteracting IAV replication. Antioxid. Redox signal. 00, 000-000.
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Adaptive mutations in the H5N1 polymerase complex.
Virus Res.
PUBLISHED: 04-04-2013
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Adaptation of the viral polymerase to host factors plays an important role in interspecies transmission of H5N1 viruses. Several adaptive mutations have been identified that, in general, determine not only host range, but also pathogenicity and transmissibility of the virus. The available evidence indicates that most of these mutations are found in the PB2 subunit of the polymerase. Particularly prominent mutations are located in the C-terminal domain of PB2 involving the amino acid exchanges E627K and D701N. Both mutations, that are also responsible for the adaptation of other avian viruses to mammalian hosts, have been described in human H5N1 isolates. In animal models, it could be demonstrated that they enhance pathogenicity in mice and induce contact transmission in guinea pigs. Mutation E627K has also been identified as a determinant of air-borne H5N1 transmission in ferrets. We are only beginning to understand the underlying mechanisms at the molecular level. Thus, mutation D701N promotes importin-? mediated nuclear transport in mammalian cells. Mutation E627K also enhances the replication rate in an importin-? dependent fashion in mammalian cells, yet without affecting nuclear entry of PB2. Numerous other adaptive mutations, some of which compensate for the lack of PB2 E627K, have been observed in PB2 as well as in the polymerase subunit PB1, the nucleoprotein NP, and the nuclear export protein NEP (NS2).
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2009 pandemic H1N1 influenza A virus strains display differential pathogenicity in C57BL/6J but not BALB/c mice.
Virulence
PUBLISHED: 11-01-2011
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Influenza A viruses are the causative agents of annual epidemics and occasional pandemics. The pathogenicity of influenza viruses is determined by complex interplay of viral and host factors. While some knowledge exists on viral determinants of pathogenicity, little is known on the host factors involved. Here, we discuss our recent findings on host genetic variations involved in disease outcome. We found that 2009 pandemic H1N1 influenza A virus strains (pH1N1) are low pathogenic in BALB/c but display differential pathogenicities in C57BL/6J mice. In contrast, a highly pathogenic avian influenza A virus (HPAIV) strain of the H5N1 subtype isolated from a fatal human case was more virulent in BALB/c than C57BL/6J mice. As a control, we used a seasonal H1N1 influenza virus which showed marginal pathogenicity in both mouse strains. Thus, differences in pH1N1 virulence become visible in C57BL/6J mice, while intrinsic pH1N1 pathogenicity markers are masked in BALB/c mice. Further, increased pH1N1 virulence correlated with a depressed cytokine response in C57BL/6J mice, while increased H5N1 virulence correlated with an elevated proinflammatory cytokine response in BALB/c mice. These findings indicate that disease severity can be strongly regulated by the host genetic background. Moreover, our findings suggest that differential host determinants contribute to the pathogenesis of pH1N1 and human H5N1 influenza viruses. Further studies are needed to identify the responsible viral factors involved in enhanced pH1N1 virulence in C57BL/6J mice. Also, extensive studies are needed to identify and characterize cellular factors regulating pH1N1 or H5N1 susceptibility in a host dependent manner. These observations extend our knowledge on influenza virus pathogenicity and highlight the role of host dependent factors, especially in pH1N1 susceptibility. We propose the C57BL/6J mouse strain as a convenient small animal model to study pH1N1 virulence determinants. Furthermore, the C57BL/6J mouse strain might also represent a suitable model for the assessment of pH1N1 vaccine candidates or the evaluation of antiviral therapies.
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Differential host determinants contribute to the pathogenesis of 2009 pandemic H1N1 and human H5N1 influenza A viruses in experimental mouse models.
Am. J. Pathol.
PUBLISHED: 02-09-2011
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Influenza viruses are responsible for high morbidities in humans and may, eventually, cause pandemics. Herein, we compared the pathogenesis and host innate immune responses of a seasonal H1N1, two 2009 pandemic H1N1, and a human H5N1 influenza virus in experimental BALB/c and C57BL/6J mouse models. We found that both 2009 pandemic H1N1 isolates studied (A/Hamburg/05/09 and A/Hamburg/NY1580/09) were low pathogenic in BALB/c mice [log mouse lethal dose 50 (MLD(50)) >6 plaque-forming units (PFU)] but displayed remarkable differences in virulence in C57BL/6J mice. A/Hamburg/NY1580/09 was more virulent (logMLD(50) = 3.5 PFU) than A/Hamburg/05/09 (logMLD(50) = 5.2 PFU) in C57BL/6J mice. In contrast, the H5N1 influenza virus was more virulent in BALB/c mice (logMLD(50) = 0.3 PFU) than in C57BL/6J mice (logMLD(50) = 1.8 PFU). Seasonal H1N1 influenza revealed marginal pathogenicity in BALB/c or C57BL/6J mice (logMLD(50) >6 PFU). Enhanced susceptibility of C57BL/6J mice to pandemic H1N1 correlated with a depressed cytokine response. In contrast, enhanced H5N1 virulence in BALB/c mice correlated with an elevated proinflammatory cytokine response. These findings highlight that host determinants responsible for the pathogenesis of 2009 pandemic H1N1 influenza viruses are different from those contributing to H5N1 pathogenesis. Our results show, for the first time to our knowledge, that the C57BL/6J mouse strain is more appropriate for the evaluation and identification of intrinsic pathogenicity markers of 2009 pandemic H1N1 influenza viruses that are "masked" in BALB/c mice.
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Differential use of importin-? isoforms governs cell tropism and host adaptation of influenza virus.
Nat Commun
PUBLISHED: 01-20-2011
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Influenza A viruses are a threat to humans due to their ability to cross species barriers, as illustrated by the 2009 H1N1v pandemic and sporadic H5N1 transmissions. Interspecies transmission requires adaptation of the viral polymerase to importin-?, a cellular protein that mediates transport into the nucleus where transcription and replication of the viral genome takes place. In this study, we analysed replication, host specificity and pathogenicity of avian and mammalian influenza viruses, in importin-?-silenced cells and importin-?-knockout mice, to understand the role of individual importin-? isoforms in adaptation. For efficient virus replication, the polymerase subunit PB2 and the nucleoprotein (NP) of avian viruses required importin-?3, whereas PB2 and NP of mammalian viruses showed importin-?7 specificity. H1N1v replication depended on both, importin-?3 and -?7, suggesting ongoing adaptation of this virus. Thus, differences in importin-? specificity are determinants of host range underlining the importance of the nuclear envelope in interspecies transmission.
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Spread of infection and lymphocyte depletion in mice depends on polymerase of influenza virus.
Am. J. Pathol.
PUBLISHED: 08-21-2009
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SC35M is a mouse-adapted variant of the highly pathogenic avian influenza virus SC35. We have previously shown that interspecies adaptation is mediated by mutations in the viral polymerase and that it is paralleled by the acquisition of high pathogenicity for mice. In the present study, we have compared virus spread and organ tropism of SC35 and SC35M in mice. We show that SC35 virus causes mild bronchiolitis in these animals, whereas infection with the mouse-adapted SC35M virus leads to severe hemorrhagic pneumonia with dissemination to other organs, including the brain. In SC35M-infected animals, viral RNA and viral antigen were detected in monocytes and macrophages, and SC35M, unlike SC35, replicated in lymphocyte and macrophage cultures in vitro. SC35M did not induce an adequate cytokine response but, unlike SC35, caused severe lymphopenia in mice. These observations suggest that the high efficiency of the SC35M polymerase is responsible for infection and depletion of lymphocytes and other white blood cells, which results in immune suppression and systemic virus spread.
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DNA vaccination with a single-plasmid construct coding for viruslike particles protects mice against infection with a highly pathogenic avian influenza A virus.
J. Infect. Dis.
PUBLISHED: 06-10-2009
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With seasonal outbreaks affecting millions of people each year and devastating pandemics, human influenza is a major health concern. The pandemic threat includes highly pathogenic avian influenza viruses (HPAIVs) that gained the ability to infect humans in Asia and quickly spread throughout the world. Major concerns have been raised regarding todays vaccine production systems against influenza viruses, and new strategies to design efficient vaccines are under intensive investigation.
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Antibody prevalence to the 2009 pandemic influenza A (H1N1) virus in Germany: geographically variable immunity in winter 2010/2011.
Med. Microbiol. Immunol.
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Location- and age-specific prevalence of antibodies against 2009 pandemic influenza A (H1N1) virus were determined in sera of blood donors collected during winter 2010/2011 in Germany. Prevalence of antibodies at protective titres (HI ?1:40) varied significantly between cities (24.13-83.67 %) throughout all age groups. However, high level antibodies (HI >1:80) were most prevalent among young individuals (18-29 and 30-39 years). Overall, this study demonstrates that older people (50-59 and 60-70 years) are no longer more likely to present protective antibody titres against 2009 pandemic influenza A (H1N1) virus than younger individuals. Furthermore, our data show a highly variable immunity among the German population in different major cities almost 2 years after the detection of first cases in Germany.
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Interaction of influenza A virus matrix protein with RACK1 is required for virus release.
Cell. Microbiol.
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The mechanism of budding of influenza A virus revealed important deviation from the consensus mechanism of budding of retroviruses and of a growing number of negative-strand RNA viruses. This study is focused on the role of the influenza A virus matrix protein M1 in virus release. We found that a mutation of the proline residue at position 16 of the matrix protein induces inhibition of virus detachment from cells. Depletion of the M1-binding protein RACK1 also impairs virus release and RACK1 binding requires the proline residue at position 16 of M1. The impaired M1-RACK1 interaction does not affect the plasma membrane binding of M1; in contrast, RACK1 is recruited to detergent-resistant membranes in a M1-proline-16-dependent manner. The proline-16 mutation in M1 and depletion of RACK1 impairs the pinching-off of the budding virus particles. These findings reveal the active role of the viral matrix protein in the release of influenza A virus particles that involves a cross-talk with a RACK1-mediated pathway.
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Human-like PB2 627K influenza virus polymerase activity is regulated by importin-?1 and -?7.
PLoS Pathog.
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Influenza A viruses may cross species barriers and transmit to humans with the potential to cause pandemics. Interplay of human- (PB2 627K) and avian-like (PB2 627E) influenza polymerase complexes with unknown host factors have been postulated to play a key role in interspecies transmission. Here, we have identified human importin-? isoforms (?1 and ?7) as positive regulators of human- but not avian-like polymerase activity. Human-like polymerase activity correlated with efficient recruitment of ?1 and ?7 to viral ribonucleoprotein complexes (vRNPs) without affecting subcellular localization. We also observed that human-like influenza virus growth was impaired in ?1 and ?7 downregulated human lung cells. Mice lacking ?7 were less susceptible to human- but not avian-like influenza virus infection. Thus, ?1 and ?7 are positive regulators of human-like polymerase activity and pathogenicity beyond their role in nuclear transport.
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